Hydantoin derivatives

ABSTRACT

The present invention relates to novel hydantoin derivatives, processes for producing said hydantoin derivatives, pharmaceutical compositions containing at least one of said hydantoin derivatives as aldose reductase inhibitors and novel intermediate compounds in the synthesis of said hydantoin derivatives. 
     The present invention is based on the selection of a hydantoin which is bonded by a sulfonyl group to various substituents at the 1-position of the hydantoin skeleton. 
     The compounds of the present invention have a strong inhibitory activity against aldose reductase. These compounds are extremely useful for the treatment and/or prevention of various forms of diabetic complications based on the accumulation of polyol metabolites.

This is a divisional application of U.S. Ser. No. 07/426,021 filed Oct.24, 1989, now U.S. Pat. No. 5,004,751 which in turn was acontinuation-in-part divisional application of U.S. Ser. No. 07/235,557,filed Aug. 24, 1988, now U.S. Pat. No. 4,914,099.

BACKGROUND OF THE INVENTION

The present invention relates to novel hydantoin derivatives, processesfor producing hydantoin derivatives, pharmaceutical compositionscontaining at least one of said hydantoin derivatives as aldosereductase inhibitors and novel intermediate compounds in the synthesisof said hydantoin derivatives.

Cataract, peripheral neuropathy, retinopathy and nephropathy associatedwith diabetes mellitus result from abnormal accumulation of polyoimetabolites converted from sugars by aldose reductase. For example,sugar cataract results from damage of lens provoked by change in osmoticpressure induced by abnormal accumulation of polyol metabolitesconverted from glucose or galactose by aldose reductase in lens. [see J.H. Kinoshita et al., Biochim. Biophys. Acta, 158, 472 (1968) and citedreferences in the report]. And some reports were submitted aboutundesirable effect of abnormal accumulation of polyol metabolites inlens, peripheral nerve cord and kidney of the diabetic animals [see A.Pirie et al. Exp. Eye Res., 3, 124 (1964) L. T. Chylack Jr. et at.,Invest. Opthal., 8,401 (1969) J. D. Ward el al, Diabetologia, 6, 531(1970)]. Consequently, it is important to inhibit aldose reductase asstrongly as possible for treating and/or preventing diabeticcomplications mentioned above. Although several compounds have beenoffered as aldose reductase inhibitors, none of them is fully sufficientin inhibitory activity against the enzyme. Therefore, it has beendesired to develop new compounds having a stronger inhibitory activityagainst aldose reduetase.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel hydantoinderivatives and salts, solvates and solvates of salts thereof.

Another object of the present invention is to provide processes forproducing said novel hydantoin derivatives.

A further object of the present invention is to provide pharmaceuticalcompositions comprising at least one of said novel hydantoin derivativeshaving an inhibitory activity against aldose reductase.

A further object of the present invention is to provide novelintermediate compounds in the synthesis of said novel hydantoinderivatives.

The present inventors previously found that substitutedphenylsulfonylhydantoin derivatives and naphthalenylsulfonylhydantoinderivatives had a strong inhibitory activity against aldose reductaseand accomplished an invention on aldore reductase inhibitors. (JP-A-56213518, 60 207113, 61 43770)

The present inventors previously found that sulfonylhydantoinderivatives had a strong inhibitory activity against aidose reductaseand accomplished an invention on aldose reductase inhibitors (JP kokai58 109418, 62 67075, 62 201873 and 1 61465). And M. S. Malamas et al.U.S. Pat. No. 4,743,611 disclosed naphthalenesulfonyl hydantoinderivatives useful as aldose reductase inhibitors. And Ohishi et al.disclosed benzofuranylsulfonyl glycine derivatives useful as drugs oftreatment of diabetic complications (JP Kokai 62 155269).

Furthermore, the present inventors have made extensive researches on aseries of compounds having an inhibitory activity against aldosereductase and found novel hydantoin derivatives having an extremelystrong inhibitory activity against aldose reductase. They are extremelyusful for the treatment and/or prevention of various forms of diabeticcomplications based on the accumulation of polyol metabolites.

DETAILED DESCRIPTION OF THE INVENTION

As a result of extensive investigations concerning development ofhydantoin derivatives having a satisfactory inhibitory activity againstaldose reductase, the present inventors have found that novel hydantoinderivatives represented by the general formula (I) satisfy thisrequirement and have accomplished the present invention.

The present invention is based on the selection of a hydantoin which isbonded by or through a sulfonyl group to various substituents at the1-position of the hydantoin skeleton.

The present invention is directed to novel hydantoin derivativesrepresented by the general formula (I): ##STR1## and non-toxic salts,solvates and solvates of non-toxic salts thereof; wherein Q representsan alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3to 6 carbon atoms, a biphenylyl group, a mono- or a fused heterocyclicgroup which may be substituted by one or more substituents which aresame or different and selected from a group consisting of a halogenatom, a lower alkyl group, a nitro group, a cyano group, an optionallyprotected carboxy group, an optionally protected carboxymethyl group, ahalogenated lower alkyl group, a lower alkylthio group, a loweralkylcarbonyl group, a lower alkoxy group, a lower alkylsulfinyl group,a lower alkylsulfonyl group, an optionally protected hydroxy group, anoptionally protected amino group, a carbamoyi group and a phenyl groupor a group: ##STR2## wherein R¹ represents an andno group which may besubstituted with lower alkyl groups and/or acyl groups, a halogen atom,a lower alkyl group, an alkoxy group, a nitro group or a cyano group, orcombination of any of these groups when n represents an integer of 2 ormore, and n represents an integer of 1, 2, 3 or 4.

The present invention is also directed to the process for preparingabove-mentioned hydantoin derivatives.

The present invention is further directed to pharmaceutical compositionscharacterized by containing at least one of these hydantoin derivativesas active component(s).

The present invention is further directed to novel intermediatecompounds in the synthesis of above-mentioned hydantoin derivatives.

Compounds of the present invention and non-toxic salts, solvates andsolvates or non-toxic salts thereof represents a satisfactory inhibitoryactivity against aldose reductase and a preventing activity againstcataracts, neuropathy in experimental animal models.

Compounds of the present invention and non-toxic salts, solvates andnon-toxic salts thereof are free of central nervous system side effectssuch as anti-convulsant activity and low toxicity, so useful for thetreatment and/or prevention of various forms of diabetic complicationssuch as neuropathy, autonomic disease, cataract, retinopathy, neuropathyand microvascular disease.

In the hydantoin derivatives of the present invention represented by thegeneral formula (I), it is known that the hydantoin moiety exhibitstautomerism as shown below: ##STR3##

Since these tautomeric isomers are generally deemed to be the samesubstance, the compounds of the present invention represented by thegeneral formula (I) also include all of these tautomeric isomers.

The compounds represented by the general formula (I) may form salts withbase. Typical examples of salts with base of the compounds representedby the general formula (I) include pharmaceutically acceptable saltssuch as alkali metal salts (such as sodium salts, potassium salts,etc.), alkaline earth metal salts (such as magnesium salts, calciumsalts, etc.), salts with organic bases (such as ammonium salts,benzylamine salts, diethylamine salts, etc.) or salts of amino acids(such as arginine salts, lysine salts, etc.). These salts of thecompounds represented by the general formula (I) may be mono-salts ordi-salts which may be salts of the hydantoin moiety and/or salts of thecarboxy group contained in the Q group.

The compounds represented by the general formula (I) may also form acidaddition salts. Typical example of acid addition salts of the compoundsrepresented by the general formula I) include pharmaceuticallyacceptable salts, such as salts of inorganic acids (such ashydrochlorides, hydrobromides, sulfates, phosphates, etc.), salts oforganic acids (such as acetates, citrates, maleates, tartrates,benzoates, ascorbate, ethanesulfonates, toluene-sulfonates, etc.) orsalts of amino acids (such as aspartates, glutamates, etc.). These saltsof the compounds represented by the general formula (I) may be salts ofthe heterocyclic moiety in the Q group.

In the compounds of the present invention represented by the generalformula (I), the lower alkyl group can be defined more specifically as astraight or branched lower alkyl group having 1 to 4 carbon atoms suchas methyl, ethyl, isopropyl, tert-butyl, etc. The alkoxy group can bedefined more specifically as a straight branched lower alkoxy grouphaving 1 to 4 carbon atoms such as methoxy, ethoxy, tert-butoxy, etc.The acyl group can be defined more specifically as a straight orbranched lower acyl group having 1 to 5 carbon atoms such as formyl,acetyl, propanoyl, butanoyl, pivaloyl, etc.

In the compounds of the present invention represented by the generalformula (I), the heterocyclic group can be defined as a monocyclicheterocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiazolinyl, thiadiazolyl, thiatriazolyl, thienyl(thiophenyl), furyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl,pyridyl or its N-oxide, pyrazinyl, pynmidinyl, pyridazinyl, piperidyl,piperazinyl, morpholinyl, triazinyl, etc., or a fused heterocyclic groupsuch as indolyl, isoindolyl, benzimidazolyl, quinolyl, isoquinolyl,quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, indazolyl,benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzisoxazolyl, benzisothiazolyl, benzothiophenyl(benzo[b]thiophenyl or benzo[c]thiophenyl)-(benzothienyl(benzo[b]thienyl or benzo[c]thienyl)), tetrahydrobenzothiophenyl(tetrahydrobenzothienyl), benzofuranyl (benzo[b]furanyl orisobenzofuranyl), chromenyl, chromanyl, coumarinyl, chromonyl,triazolopyridyl, tetrazolopyridyl, purinyl, thiazolopyrimidinyl,triazolopyrimidinyl, thiadiazolopyrmidinyl, thiazolopyridazinyl,naphthyridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl,carbazolyl, etc. preferably indolyl, benzimidazolyl, benzotriazolyl,benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzothiophenyl,tetrahydrobenzothiophenyl, benzofuranyl, coumarinyl, chromonyl, morepreferably benzo[b]thiophenyl or benzo[b]furanyl. The above-mentionedheterocyclic groups may be substituted with a group such as a loweralkyl group (such as methyl, ethyl, isopropyl, tert-butyl, etc.), alower alkylcarbonyl group (such as acetyl, propanoyl, butanoyl, etc.), alower alkoxy group (such as methoxy, ethoxy, isopropoxy, tert-butoxy,etc.), a phenyl group, a cyano group, a carbamoyl group, an optionallyprotected carboxy group, an optionally protected carboxymethyl group, anitro group, a halogenated lower alkyl group (such as trifluoromethyl,pentafluoroethyl, etc.), an optionally protected hydroxy group, anoptionally protected amino group, (such as acyl amino, etc.), a loweralkylthio group, a lower alkylsulfinyl group, a lower alkyl sulfonylgroup or a halogen atom (such as fluoro, chloro, bromo, iodo etc.), orcombination of any of these groups.

In a mono- heterocyclic group, a compound unsubstituted or substitutedwith 1 or 2 substituents which are the same or different and selectedfrom a group consisting of a halogen atom or phenyl group, ispreferable.

In a fused heterocyclic group, a compound unsubstituted or substitutedwith 1 to 3 substituents which are the same or different and selectedfrom a group consisting of a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkylthio group or a cyano group,is preferable.

When a fused heterocyclic group is a benzo[b]furan-2-yl group which maybe substituted, the said substituents are preferably 1 to 3 halogenatoms.

The compounds of the present invention represented by the formula (I)can be produced by the processes described as follows.

Namely,

The starting material of sulfonyl halide represented by the formula(II):

    Q--SO.sub.2 --Y                                            (II)

wherein Q has the same significance as defined above, and Y represents ahalogen atom, is prepared as follows.

A compound Q--H wherein Q has the same significance as defined above andH represents a hydrogen atom is reacted with a base (such asn-butyllithium or lithium diisopropylamide, etc.) and sulfur dioxide andthen reacted with a halogenating reagent (such as chlorine, bromine,phosphorus pentachloride, thionyl chloride, N-chlorosuccinimide orN-bromosuccinimide, etc.) to obtain an objective compound.

Further, Q--H wherein Q has the same significance as defined above isreacted with a halosulfonic acid (preferably chlorosulfonic acid, etc.)to obtain directly an objective compound.

Further, a sulfonic acid derivative of Q--H (Q--SO₃ H) wherein Q has thesame significance as defined above is reacted with sodium bicarbonate togive a corresponding salt, and then reacted with a halogenating reagent(such as phosphorus pentachloride, thionyl chloride or thionyl bromide,etc.) to obtain an objective compound.

Further, a S-benzyl derivative of Q--H (Q--S--CH₂ C₆ H₅) wherein Q hasthe same significance as defined above is reacted with a halogenatingreagent (such as chlorine, etc.) to obtain an objective compound.

Further, an amine derivative of Q--H (Q--NH₂) wherein Q has the samesignificance as defined above is reacted whh a nitrite salt (such assodium nitrite, etc.), and then reacted with sulfur dioxide and ahalogcnating reagent (such as copper (I) chloride or copper (II)chloride, etc.) to obtain an objective compound.

The sulfonyl halide derivative, obtained above mentioned procedure isreacted with a glycine derivative represented by the formula (III):

    NH.sub.2 CH.sub.2 CO--R                                    (III)

wherein R represents a hydroxy group, an alkoxy group or an amino groupwhich may be substituted by an alkoxycarbonyl group, to give thecorresponding sulfonylglycine derivative represented by the formula(IV):

    Q--SO.sub.2 NHCH.sub.2 CO--R                               (IV)

wherein Q and R have the same significance as defined above. Such acondensation reaction is carried out generally in an aqueous solution,in an organic solvent (such as dichloromethane, chloroform, dioxane,tetrahydrofuran, acetonitrile, ethyl acetate, acetone,N,N-dimethylformamide, etc.) or in a mixed solvent of an aqueoussolution and an organic solvent, preferably in the presence ofdeacidifying agent. As the deacidifying agent, triethylamine,diethylaniline, pyridine, etc. is employed in the organic solventsystem, and in the aqueous system, aqueous alkali (such as sodiumcarbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide,etc.) is employed. The condensation reaction is carried out attemperatures ranging from about -20° to 80° C., preferably 0° C. to roomtemperature.

When R represents an amino group in the formula (IV), thesulfonylglycine derivative is represented by the formula (V):

    Q--SO.sub.2 NHCH.sub.2 CONH.sub.2                          (V)

wherein Q has the same significance as defined above.

The sulfonylglycine derivative represented by the formula (V) iscyclized using a haloformic acid ester (such as methyl chloroformate,ethyl chloroformate, etc.) in the presence of a base (such as sodiumhydride, potassium hydride, butyllithium, etc.) to give thecorresponding hydantoin derivative of the present invention representedby the formula (I). The cyclization reaction is carried out generally inan inert solvent (such as N,N-dimethylformamide, dimethylsulfoxide,ethyl ether, tetrahydrofuran, dioxane, dichloromethane, etc.) and attemperatures ranging from about -20° to 120° C., preferably 0° to 80° C.

When R represents an amino group protected with an alkoxycarbonyl group,the sulfonylglycine derivative is cyclized in the presence of a base(such as sodium hydride etc.) to give the corresponding hydantoinderivative of the present invention represented by the formula (I).

When R represents a hydroxy group or an alkoxy group in the formula(IV), the sulfonylglycine derivative is represented by the formula (VI):

    Q--SO.sub.2 NHCH.sub.2 CO--R.sup.1                         (VI)

wherein Q has the same significance as defined above and R¹ represents ahydroxy group or an alkoxy group. The sulfonylglycine derivativerepresented by the formula (VI) is cyclized with a thiocyanatederivative (such as ammonium thiocyanate, potassium thiocyanate, etc.)in the presence of an acid anhydride (such as acetic anhydride,propionic anhydride. etc.) and. if necessary and desired, a base (suchas pyridine, triethylamine, etc.) to give the corresponding2-thiohydantoin derivative. If necessary and desired, the cyclizationreaction is carried out after hydrolysis of ester when R¹ represents analkoxy group. The cyclization reaction is carried out generally in aninert solvent (such as pyridine, triethylamine, N,N-dimethylformamide,dimethylsulfoxide, etc.) and at temperatures ranging from 0° to 120° C.,preferably room temperature to 100° C. Further, the 2-thiohydantoinderivative obtained by said cyclization is oxidized using oxidizingagent (such as nitric acid, chlorine, iodine chloride, potassiumpermanganate, hydrogen peroxide, dimethylsulfoxide-sulfuric acid, etc.)to give the corresponding hydantoin derivatives of the present inventionrepresented by the formula (I).

To demonstrate the utility of the compounds of the present invention,experimental examples of representative compounds are shown below.

Compounds in the present invention

Compound 1: 1-(1-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 2: 1-(3-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 3: 1-(5-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 4: 1-(6-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 5: 1-(7-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 6: 1-(8-chloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 7: 1-(3,6-dichloronaphthalen-2-ylsulfonyl)-hydantoin

Compound 8: 1-(1-bromonaphthalen-2-ylsulfonyl)-hydantoin

Compound 9: 1-(3-bromonaphthalen-2-ylsulfonyl)-hydantoin

Compound 10: 1-(6-bromonaphthalen-2-ylsulfonyl)-hydantoin

Compound 11: 1-(5-nitronaphthalen-2-ylsulfonyl)-hydantoin

Compound 12: 1-(3-methylnaphthalen-2-ylsulfonyl)-hydantoin

Compound 13: 1-(6-methyl-5-nitronaphthalen-2-ylsulfonyl)hydantoin

Compound 14: 1-(7-methylnaphthalen-2-ylsulfonyl)-hydantoin

Compound 15: 1-(6-methoxy-5-nitronaphthalen-2-ylsulfonyl)hydantoin

Compound 16: 1-(benzo[b]thiophen-2-ylsulfonyl)-hydantoin

Compound 17: 1-(3-chlorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 18: 1-(5-chlorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 19: 1-(benzo[b]furan-2-ylsulfonyl)hydantoin

Compound 20: 1-(5-chlorobenzo[b]furan-2-ylsulfonyl)-hydantoin

Compound 21: 1-(5-bromobenzo[b]furan-2-ylsulfonyl)-hydantoin

Compound 22: 1-(benzothiazol-2-ylsulfonyl)hydantoin

Compound 23: 1-(coumarin-6-ylsulfonyl)hydantoin

Compound 24: 1-(2,5-dichlorothiophen-3-ylsulfonyl)-hydantoin

Compound 25: 1-(4,5-dibromothiophen-2-ylsulfonyl)-hydantoin

Compound 26: 1-(6-chlorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 27: 1-(7-chlorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 28: 1-(3-isopropylbenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 29: 1-(3-trifluoromethylbenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 30: 1-(3-bromobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 31: 1-(3-methoxybenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 32: 1-(3-methylsulfonylbenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 33: 1-(3-cyanobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 34: 1-(3-bromo-7-fluorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 35: 1-(2-chlorobenzo[b]thiophen-3-ylsulfonyl)hydantoin

Compound 36: 1-(4-iodobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 37: 1-(4,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 38: 1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 39: 1-(5-fluorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 40: 1-(4-chlorobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 41: 1-(benzo[b]isothiazol-3-ylsulfonyl)hydantoin

Compound 42: 1-(5-nitrobenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 43: 1-(5-carboxybenzo[b]thiophen-2-ylsulfonyl)hydantoin

Compound 44: 1-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 45: 1-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 46:1-(3-bromo-4,6-dichlorobertzo[b]furan-2-ylsulfonyl)hydantoin

Compound 47: 1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 48: 1-(7-fluorobenzo[b]furan-2-ylsulfonyl)hydantoin

Compound 49: 1-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)hydantoin

REFERENCE COMPOUNDS

Compound A: 1-(naphthalene-2-ylsulfonyl)hydantoin

Compound B: sorbinil:[(S)-6-Fluoro-2,3-dihydrospiro(4H-1-benzopyran4,4'-imidazolidine)-2',5'-dione] (synthesized by the method of R. S. sarges et al.: see J. Med.Chem., 28, 1716 (1985))

EXPERIMENTAL EXAMPLE 1

The inhibitory activities of hydantoin derivatives on rat lens aldosereductase were measured according to the procedure of Inagaki et al. CK.Inagaki et al., Arch. Biochem. Biophys., 216, 337 (1982)) with slightmodifications. Assays were performed in 0.1 M phosphate buffer (pH 6.2)containing 0.4 M ammonium sulfate, 10 mM DL-glyceraldehyde, 0.16 mMnicotinamide adenine dinucleotide phosphate, reduced form (NADPH) andaldose reductase (0.010-0.016 units) in a total volume of 1.0 mi. Tothis mixture was added 10 μl of the solution of each hydantoinderivative to be tested, and the decrease in absorbance at 340 nm wasmeasured with a spectrophotometer.

The concentrations of typical hydantoin derivatives of the presentinvention required to produce 50% inhibition are shown in table 1.

                  TABLE 1                                                         ______________________________________                                                 Compounds                                                                             IC.sub.50 (μmol/l)                                        ______________________________________                                                 1       0.29                                                                  2       0.16                                                                  3       0.19                                                                  4       0.14                                                                  5       0.39                                                                  6       0.46                                                                  7       0.24                                                                  8       0.094                                                                 9       0.35                                                                  10      0.17                                                                  11      0.10                                                                  12      0.14                                                                  13      0.027                                                                 14      0.35                                                                  15      0.038                                                                 A       0.66                                                         ______________________________________                                    

Compounds 1 to 15 of the present invention showed stronger inhibitoryactivities against aldose reductase than reference compound A did. Aboveall, compound 13 and 15 were ten times or more potent than referencecompound A.

EXPERIMENTAL EXAMPLE 2

The inhibitory activities of hydantoin derivatives on bovine lens aldosercductase were measured according to the procedure of Inagaki et al. (K.Inagaki et al., Arch. Blochcm. Biophys., 216, 337 (1982)) with slightmodifications. Assay procedure was the same as described in Experimentalexample 1 except that bovine lens aldose reductsse preparation was usedinstead of rat lens aldose reductase preparation.

The concentrations of the typical hydantoin derivatives of the presentinvention required to produce 50% inhibition are shown in table 2.

                  TABLE 2                                                         ______________________________________                                        Compounds     IC.sub.50 (μmol/l)                                           ______________________________________                                        13            0.10                                                            15            0.23                                                            16            0.39                                                            17            0.12                                                            18            0.24                                                            20            0.36                                                            21            0.30                                                            22            0.34                                                            23            0.22                                                            24            0.29                                                            25            0.26                                                            26            0.27                                                            27            0.19                                                            28            0.14                                                            29            0.13                                                            30            0.12                                                            31            0.27                                                            32            0.38                                                            33            0.19                                                            34            0.085                                                           35            0.30                                                            36            0.24                                                            37            0.17                                                            38            0.16                                                            39            0.32                                                            40            0.17                                                            41            0.47                                                            42            0.27                                                            43            0.40                                                            44            0.061                                                           45            0.083                                                           46            0.054                                                           B             0.65                                                            ______________________________________                                    

Compounds 13, 15, 16 to 18, 20 to 46 of the present invention showedstronger inhibitory activities against aldose reductase than referencecompound B did, which is a well known potent aldose reductase inhibitor.Compound 17, 18, 23 and 24 were as potent as compound 13 and 15, whichshowed strongest inhibitory activities in experimental example 1. Aboveall, several compounds were ten times or more potent than referencecompound B.

EXPERIMENTAL EXAMPLE 3

Hydantom derivatives of the present invention were examined for acutetoxicity. Groups of 5 ICR strain mice were orally administered withcompound 7, 13 to 17, 19, 20, 21, 24, 38, 40, 44, 45, 47 to 49 of thepresent invention in a dose of 1 g/kg, and no change was observed in anyof the groups over the one-week period after the administration.

Since the compounds of the present invention have strong inhibitoryactivities against aldose reductase, show lower toxicity and showstronger preventing activities against cataracts, neuropathy in animalmodels than known compounds, pharmaceutical compositions containing atleast one of these compounds as active component(s) are useful for thetreatment and/or prevention of diabetic complication based on theaccumlation of polyol metabolites.

The hydantoin derivatives provided by the present invention can beemployed as pharmaceutical compositions, for example, in the form ofpharmaceutical compositions containing hydantoin derivatives togetherwith appropriate pharmaceutically acceptable carrier or medium such assterilized water, edible oils, non-toxic organic solvents or non-toxicsolubilizer such as glycerin or propylene glycol. They may be mixed withexcipients, binders, lubricants, coloring agents, corrigents,emulsifying agents or suspending agents such as Tween 80 or arabic gumto prepare tablets, capsules, powders, granules, subtilized granules,syrups, eye drops, suppositories, ointments, inhalants, aqueous or oilysolutions or emulsion or suspensions for injections. These agents can beadministered either orally or parenterally (such as intravenousadministration, intramuscular administration, subcutaneousadministration, intrarectal administration, percutaneous administrationor permucosal administration etc.), and the amount of administration maybe in the range of 1 to 3000 mg/day, preferably 10 to 500 rag/day whenthe preparation is tablets, capsules, powders, injections,suppositories, syrups, inharants or ointments, 1 μg to 10 mg/day,preferably 10 μmg to 1 mg/day when the preparation is eye drops, and 1to 10% composition when the preparation is ointments, and may also beadjusted according to the patient conditions and can administered onceor divided 2 to 6 times or by instillation, etc.

Hereafter the present invention will be described with references to theexamples below but is not deemed to be limited thereof.

EXAMPLE 1 Preparation of 1-(1-chloronaphthalen-2-ylsulfonyl)hydantoin(compound I) Step 1 Preparation ofN-(1-chloronaphthalen-2-ylsulfonyl)glycine

To a solution of potassium carbonate (21 g) and glycine (11 g) in water(300 ml) was added 1-chloronaphthalen-2-ylsulfonyl chloride (31 g) atroom temperature, and the mixture was stirred under reflux for 30minutes.

After cooling to room temperature, the resultant solution was acidifiedwith 2 N hydrochloric acid to a pH in the range of 1 to 2, and theformed precipitate was separated by filtration to give 33 g of theobjective compound.

Melting point: 185.5°-200.7° C.

IR (KBr, cm⁻¹): 3380, 1720, 1325, 1135

NMR (DMSO-d₆, ppm): 3.63 (2H, s), 7.59-8.51 (7H, m)

Step 2 Preparation of1-(1-chloronaphthalen-2-ylsulfonyl)-2-thiohydantoin

Anhydrous pyridine (19 ml), ammonium thiocyanate (17 g) and aceticarthydride (50 ml) were added to the product obtained in Step 1 (30 g),and the mixture was heated with stirring on a boiling water bath for 15minutes. After cooling to room temperature, the resultant solution waspoured into ice-water (300 ml), and the formed precipitate was separatedby filtration to give 30.6 g of the objective compound.

Melting point: 268.6° C. (decomposition)

IR (KBr, cm⁻¹ : 3150, 1790, 1765, 1380, 1190

NMR (DMSO-d₆, ppm): 4.93 (2H, s), 7.66-8.53 (5H, m), 8.78 (1H, s)

Step 3 Preparation of 1-(1-chloronaphthalen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Step 2 (20 g) and 50% (w/v, nitricacid (100 ml) was heated with stirring on a boiling water bath for 40minutes, and the resultant solution was cooled in an ice bath. Theformed precipitate was separated by filtration and washed successivelywith water, ethyl alcohol, methyl alcohol and dichloromethane to give4.8 g of the objective compound.

Melting point: 258.3°-260.5° C.

IR (KBr, cm⁻¹): 3140, 1740, 1310, 1180

NMR (DMSO-d₆, ppm): 4.74 (2H, s), 7.80-8.39 (6H, m), 11.77 (1H, s)

EXAMPLE 2 Preparation of 1-(1-bromonaphthalen-2-ylsulfonyl)hydantoin(compound 8) Step 1 Preparation ofN-(1-bromonaphthalen-2-ylsulfonyl)glycine

Starting from 1-bromonaphthalen-2-ylsulfonyl chloride, the objectivecompound was obtained in a manner similar to Step 1 of Example 1.

Melting point: 199.7°-204.1° C.

NMR (DMSO-d₆, ppm): 3.77 (2H, d, J=6.0 Hz), 7.49-8.47 (7H, m)

Step 2 Preparation of 1-(1-bromonaphthalen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 1, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 253.7° C. (decomposition)

NMR (DMSO-d₆, ppm): 5.01 (2H, s), 7.71-8.80 (6H, m)

Step 3 Preparation of 1-(1-bromonaphthalen-2-ylsulfonyl)hydatoin

A mixture of the product obtained in Step 2 (7.5 g) and 50% (w/v) nitricacid (50 ml) was heated with stirring on a boiling water bath for 30minutes and 60% (w/v) nitric acid (25 ml) was added. The reactionmixture was heated with stirring on a boiling water bath for 2 hours.The resultant solution was cooled in an ice bath, and the formedprecipitate was sepanted by filtration and washed successively withwater, methyl alcohol and dichloromethane to give 2.7 g of the objectivecompound.

Melting point: 287.4-292.5° C.

IR (KBr, cm⁻¹): 3200, 1740, 1310, 1180

NMR (DMSO-d₆, ppm): 4.78 (2H, s), 7.79-8.52 (6H, m), 11.75 (1H, s)

EXAMPLE 3 Preparation of1-(3,6-dichioronaphthalen-2-ylsulfonyl)hydantein (compound 7) Step 1Preparation of N-(3,6-dichloronaphthalen-2-ylsulfonyl)glycine

To a solution of potassium carbonate (11.7 g) and glycine (6.4 g) inwater (140 ml) were added 3,6-dichloronaphthalen-2-ylsulfonyl chloride(20.8 g) and dioxane (50 ml) at room temperature, and the mixture wasstirred under reflux for 2 hours. After cooling to room temperature, theresultant solution was acidified with 2N hydrochloric acid to a pH inthe range of 1 to 2, and extracted with ethyl acetate. The organic layerwas washed with water, then with saturated aqueous NaCl solution, anddried over anhydrous sodium sulfate. Ethyl acetate was removed in vacuoto give 19.0 g of the objective compound.

Melting point: 185.0°-188.2° C.

NMR (DMSO-d₆, ppm): 3.82 (2H, d, J=8.0 Hz), 7.49-8.34 (5H, m), 8.63 (1H,s)

Step 2 Preparation of1-(3,6-dichloronaphthalen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 1, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 252.8° C. (decomposition)

NMR (DMSO-d₆, ppm): 4.92 (2H, s), 7.38-8.32 (4H, m), 8.90 (1H, s)

Step 3 Preparation of 1-(3,6-dichloronaphthalen-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 3 of Example 1.

Melting point: 263.1°-266.5° C.

IR (KBr, cm⁻¹): 3220, 1740, 1355, 1170

NMR (DMSO-d₆, ppm): 4.67 (2H, s). 7.74 (1H, d), 8.18-8.43 (3H, m), 8.98(1H, s), 11.77 (1H, bs)

EXAMPLE 4 Preparation of 1-(5-nitronaphthalen-2-ylsulfonyl)hydantoin(compound 11) Step 1 Preparation ofN-(5-nitronaphthalen-2-ylsuifonyl)glycine

To a solution of potassium carbonate (3.2 g) and glycine (1.7 g) inwater (50 ml) was added 5-nitronaphthalen-2-ylsulfonyl chloride (5 g) atroom temperature, and the mixture was stirred under reflux for 5minutes. After cooling to room temperature, the resultant solution wasacidified with 2N hydrochloric acid to a pH in the range of 1 to 2, andthe formed precipitate was separated by filtration to give 5.4 g of theobjective compound.

Melting point: 235.7°-240.7° C.

IR (KBr, cm⁻¹): 3353, 1718, 1519, 1335, 1143

NMR (DMSO-d₆, ppm): 3.70 (2H, d, J=5.9 Hz), 7.73-8.64 (7H, m), 12.60(1H, bs)

Step 2 Preparation of 1-(5-nitronaphthalen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 1, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 249.6°-254.8° C.

IR (KBr, cm⁻¹): 3303, 1794, 1767, 1519, 1453, 1343, 1163

NMR (DMSO-d₆, ppm): 4.88 (2H, s), 7.8C-9.03 (6H, m), 12.67 (1H, bs)

Step3 Preparation of 1-(5-nitronaphthalen-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 3 of Example 1.

Melting point: 241.6°-245.6° C.

IR (KBr, cm⁻¹): 3265, 1801, 1737, 1523, 1340 1170

NMR (DMSO-d₆, ppm): 4.58 (2H, s), 7.81-8.96 (6H, m), 11.64 (1H, bs)

EXAMPLE 5 Preparation of 1-(6-acetamidonaphthalen-2-ylsulfonyl)hydantoinStep 1 Preparation of N-(6-acetamidonaphthalen-2-ylsulfonyl)glycine

Starting from 6-acetamidonaphthalen-2-ylsulfonyl chloride, the objectivecompound was obtained in a manner similar to Step 1 of Example 1.

Melting point: 202.2°-204.0° C.

NMR (DMSO-d₆, ppm): 2.11 (3H, s), 3.36 (2H, s), 5.01 (1H, bs), 7.58-8.40(7H, m), 10.38 (1H, bs)

Step 2 Preparation of1-(6-acetamidonaphthalen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 1, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 274.0°-276.9° C.

NMR (DMSO-d₆, ppm): 2.13 (3H, s), 4.85 (2H, s), 7.74-8.65 (6H, m), 10.30(1H, s), 12.60 (1H, bs)

Step 3 Preparation of 1-(6-acetamidonaphthalen-2-ylsulfonyl)hydantoin

To a mixture of the product obtained in Step 2 (1.45 g), sodiumbicarbonate (16 g), carbon tetrachloride (40 ml) and water (120 ml) wasadded slowly a solution of iodine monochloride (6.9 ml) in 1Nhydrochloric acid (40 ml) at room temperature. After stirring at roomtemperature for 10 minutes, 6N hydrochloric acid (320 ml) was added, andthe resultant solution was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium sulfite solution, thenwith saturated aqueous NaCl solution, and dried over anhydrous sodiumsulfate. Ethyl acetate was removed in vacuo, and the residue was washedwith dichloromethane to give 1.0 g of the objective compound.

Melting point: >300° C.

IR (KBr, cm⁻¹): 3400, 3250, 1740, 1360, 1165

NMR (DMSO-d₆, ppm): 2.14 (3H, s), 4.55 (2H, 7.60-8.56 (6H, m), 10.49(1H, s), 11.60 (1H, s)

Compounds of Example 6 to 25 prepared in a manner similar to Example 1are summarized in the following table 3 together with corresponding IRand NMR data and melting points.

                                      TABLE 3                                     __________________________________________________________________________     ##STR4##                                                                     Ex.                                                    M.P.                   No. Q                IR(KBr, cm.sup.-1)                                                                           NMR(DMSO-d.sub.6, ppm)                                                                           (°C.)           __________________________________________________________________________         ##STR5##        3250, 1735, 1350, 1160                                                                       4.57(2H, s), 7.67˜8.34(5H, m),                                          8.74(1H, s), 11.60(1H,                                                                           259.6˜262.0      7                                                                                  ##STR6##        3250, 1735, 1350, 1165                                                                       4.58(2H, s), 7.89˜8.73(6H, m),                                          11.62(1H, bs)      256.7˜261.0      8                                                                                  ##STR7##        3230, 1730, 1350, 1160                                                                       4.57(2H, s), 7.62˜8.80(6H, m),                                          11.62(1H, bs)      293.0˜299.5      9                                                                                  ##STR8##        3230, 1720, 1350, 1150                                                                       4.57(2H, s), 7.69˜8.75(6H, m),                                          11.61(1H, bs)      238.7˜241.4      10                                                                                 ##STR9##        3160, 1730, 1375, 1170                                                                       4.56(2H, s), 7.71˜8.70(6H, m),                                          11.62(1H, bs)      261.0˜263.9      11                                                                                 ##STR10##       3230, 1730, 1350, 1160                                                                       4.56(2H, s), 7.69˜8.82(6H, m),                                          11.61(1H, bs)      233.7˜235.3      12                                                                                 ##STR11##       3240, 1730, 1360, 1180                                                                       4.72(2H, s), 7.74˜8.26(4H, m),                                          8.54(1H, s), 8.96(1H, s), 11.77(1H,                                           bs)                298.0˜303.0      13                                                                                 ##STR12##       3220, 1730, 1350, 1160                                                                       4.57(2H, s), 7.80˜8.74(6H, m),                                          11.61(1H, bs)      255.6˜258.6      14                                                                                 ##STR13##       3250, 1735, 1520, 1340, 1150                                                                 3.08(3H, s), 4.58(2H,                                                         s), 7.90˜8.73(5H, m), 11.69(1H,                                         bs)                232.0˜236.5      15                                                                                 ##STR14##       3200, 1725, 1340, 1160                                                                       2.70(3H, s), 4.55(2H, s),                                                     7.62˜8.14 (5H, m), 8.75(1H, s),                                         11.65(1H, bs)      271.4˜277.3      16                                                                                 ##STR15##       3170, 1730, 1530, 1370, 1170                                                                 2.52(3H, s), 4.55(2H, s),                                                     7.74˜8.48 (4H, m), 8.85(1H, s),                                         11.62(1H, bs)      295.0˜296.1      17                                                                                 ##STR16##       3240, 1735, 1350, 1160                                                                       2.53(3H, s), 4.56(2H,                                                         s), 7.51˜8.63(6H, m), 11.58(1H,                                         bs)                212.1˜215.3      18                                                                                 ##STR17##       3180, 1740, 1530, 1370, 1170                                                                 4.11(3H, s), 4.54(2H,                                                         s), 7.75˜8.83(5H, m), 11.61(1H,                                         bs)                285.9˜286.4      19                                                                                 ##STR18##       3170, 1720, 1365, 1180                                                                       4.56(2H, s), 7.78˜8.20(6H, m),                                          11.67(1H, bs)      231.0˜234.0      20                                                                                 ##STR19##       3230, 1730, 1350, 1150                                                                       4.50(2H, s), 7.78˜8.39(6H, m),                                          11.60(1H, bs)      162.6˜166.0      21                                                                                 ##STR20##       3250, 1735, 1365, 1165                                                                       4.02(3H, s), 4.06(3H, s), 4.54(2H,                                            s), 7.72˜8.80(4H, m), 11.65(1H,                                         bs)                228.0˜230.0      22                                                                                 ##STR21##       3150, 2230, 1735, 1380, 1170                                                                 4.57(2H, s), 8.01˜8.91(5H, m),                                          11.65(1H, bs)      279.0˜285.0      23                                                                                 ##STR22##       3230, 2240, 1740, 1380, 1160                                                                 4.58(2H, s), 7.93˜8.49(4H, m),                                          8.75 (1H, s), 8.84(1H, s), 11.63(1H,                                          bs)                261.6˜264.6      24                                                                                 ##STR23##       3230, 1740, 1380, 1170                                                                       4.54(2H, s), 8.27˜8.87(3H, m),                                          11.60(1H, bs)      >300                   25                                                                                 ##STR24##       3240, 1740, 1370, 1170                                                                       2.94(6H, s), 4.53(2H,                                                         s), 7.35˜8.59(6H, m), 11.56(1H,                                         bs)                102.9˜104.5      __________________________________________________________________________

EXAMPLE 26 Preparation of 1-(benzo[b]thiophen-2-ylsulfonyl)hydantoin(compound 16) Step 1 Preparation of benzo[b]thiophen-2-ylsulfonylchloride

To a solution of benzo[b]thiophen (38.3 g) in anhydrous ether (180 ml)was added dropwise 1.6 M solution of n-butyllithium in hexane (220 ml)under ice-cooling and nitrogen atmosphere. After refluxing for 40minutes, into the solution was bubbled sulfur dioxide for 2.75 hourswith stirring at -30° C. Then the solution was stirred for 1 hour andthe formed precipitate was separated by filtration to give lithiumbenzo[b]thiophen-2-ylsulfinate. Into the suspension of the product inconcentrated hydrochloric acid (400 ml) and water (100 ml) was bubbledchlorine gas for 1.5 hours with stirring at -5° C. The resultingsolution was poured into ice-water (500 ml) and extracted withdichloromethane (1.51×2) and the organic layer was washed with saturatedaqueous NaCl solution. After drying over anhydrous magnesium sulfate,dichloromethane was removed in vacuo, and the residue was purified bysilica gel column chromatography to give 40.4 g of the objectivecompound.

IR (KBr, cm⁻¹): 1495, 1384, 1189, 1168, 1155

NMR (CDCl₃, ppm): 7.49-7.68 (2H, m), 7.86-8.03 (2H, m), 8.14 (1H, s)

Step 2 Preparation of N-(benzo[b]thiophen-2-ylsulfonyl)glycine

Starting from benzo[b]thiophen-2-ylsulfonyl chloride, the objectivecompound was obtained in a manner similar to Step 1 of Example 1.

Melting point: 171.3°-172.4° C.

IR (KBr, cm⁻¹): 3267, 1735, 1352, 1258, 1115, 1115

NMR (DMSO-d₆, ppm): 3.73 (2H, d, J=6.0 Hz), 7.39-7.61 (2H, m), 7.77-8.13(3H, m), 8.51 (1H, d, J=6.0 Hz), 12.68 (1H, bs)

Step 3 Preparation of 1-(benzo[b]thiophen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 2 or Example 1.

Melting point: 218.6° C. (decomposition)

IR (KBr, cm⁻¹): 1759, 1374, 1255, 1171, 1157

NMR (DMSO-d₆, ppm): 4.74 (2H, s), 7.35-7.69 (2H, m), 8.04-8.21 (2H, m),8.45 (1H, s), 12.72 (1H, bs)

Step 4 Preparation of 1-(benzo[b]thiophen-2-ylsulfonyl)hydantoin

To a suspension of iodine monochloride (7.12 ml) in 1 N hydrochloricacid (200 ml) were added successively the product obtained in Step 3(8.50 g) and dichloromethane (200 ml). The mixture was stirred for 20minutes at room temperature. After adding sodium bicarbonate (6.85 g),the reaction mixture was stirred for 15 minutes and extracted twice withethyl acetate (11+300 ml). The organic layer was washed with saturatedaqueous sodium bisulfite solution and then saturated aqueous NaClsolution, and dried over anhydrous magnesium sulfate. Ethyl acetate wasremoved in vacuo, the residue was washed with dichloromethane to give4.83 g of the objective compound.

Melting point: 251.8°-254 2° C.

IR (KBr, cm⁻¹): 3245, 1803, 1740, 1376, 1352, 1167

NMR (DMSO-d₆, ppm): 4.48 (2H, s), 7.51-7.63 (2H, m), 8.05-8.20 (2H, m),8.33 (1H, s), 11.71 (1H, bs)

EXAMPLE 27 Preparation of 1-(benzo[b]furan-2-ylsulfonyl)hydantoin(compound 19) Step 1 Preparation of benzo[b]furan-2-ylsulfonyl chloride

Starting from benzo[b]furan, the objective compound was obtained in amanner similar to Step 1 of Example 26.

IR (KBr, cm⁻¹): 1533, 1389, 1244, 1193, 1166

NMR (CDCl₃, ppm): 7.32-7.82 (5H, m)

Step 2 Preparation of N-(benzo[b]furan-2-ylsulfonyl)glycine

Starting from benzo[b]furan-2-ylsulfonyl chloride, the objectivecompound was obtained in a manner similar to Step 1 of Example 1.

Melting point: 177.0°-178.2° C.

IR (KBr, cm⁻¹): 3289, 1724, 1347, 1162

NMR (DMSO-d₆, ppm): 3.77 (2H, d, J=6.3 Hz), 7.35-7.81 (5H, m), 8.72 (1H,t, J=6.3 Hz), 12.69(1H, bs)

Step 3 Preparation of 1-(benzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

To a suspension of the product obtained in Step 2 (37.0 g) and ammoniumthiocyanate (24. 3 g) in acetic anhydride (100 ml) was added dropwiseanhydrous pyridine (30.5 ml), and the mixture was heated with stirringfor 1.5 hours at 70°-80° C. After cooling to room temperature, theresultant solution was poured into ice (800 g), and the formedprecipitate was separated by decantation. The precipitate was washedwith water and dried to give 18.5 g of the objective compound.

Melting point: 213.0° C. (decomposition)

IR (KBr, cm⁻¹): 3080, 1759, 1386, 1255. 1167 1096

NMR (DMSO-d₆, ppm): 4.76 (2H, s), 7.34-8.04 (5H, m), 12.81 (1H, bs)

Step 4 Preparation of 1-(benzo[b]furan-2-ylsulfonyl) hydantoin

Starting from the product obtained in Step 3, the objective compound wasobtained in a manner similar to Step 4 of Example 26.

Melting point: 255.9°-256.4° C.

IR(KBr, cm⁻¹): 1803, 1735, 1398, 1360, 1166

NMR (DMSO-d₆, ppm): 4.49 (2H, s), 7.33-8.08

Compounds of Example 28 to 52 prepared in a manner similar to Example 26are summarized in the following table 4 together with corresponding IRand NMR data and melting points.

                                      TABLE 4                                     __________________________________________________________________________     ##STR25##                                                                    Ex.                                                     M.P.                  No.                                                                              Q              IR(KBr, cm.sup.-1)                                                                           NMR(DMSO-d.sub.6, ppm) (°C.)          __________________________________________________________________________    28                                                                                ##STR26##     1803, 1755, 1516, 1372, 1350, 1165                                                           4.55(2H, s), 7.86˜9.10(6H, m),                                          11.62(1H, bs)          284.6 (dec.)          29                                                                                ##STR27##     1735, 1508, 1382, 1167                                                                       4.47(2H, s), 7.40˜8.30(3H, m),                                          8.30(1H, s), 11.73(1H,                                                                               275.2 (dec)           30                                                                                ##STR28##     1739, 1380, 1192                                                                             4.45(2H, s), 7.57˜7.69(1H, m),                                          8.15˜8.25(2H, m), 8.29(1H, s),                                          11.70(1H, bs)          >300                  31                                                                                ##STR29##     1728, 1381, 1183, 1162                                                                       4.64(2H, s), 7.58˜7.81(2H, m),                                          7.96˜8.06(1H, m),                                                       8.18˜8.29(1H, m), 11.82(1H,                                                                    278.3 (dec.)          32                                                                                ##STR30##     3270, 1741, 1379, 1162                                                                       4.51(2H, s), 7.52˜7.67(2H, m),                                          8.16˜8.23(2H, m), 11.74(1H,                                                                    271.1˜272.2     33                                                                                ##STR31##     3400, 1730, 1663, 1614, 1380, 1169                                                           3.96(2H, s), 7.61˜8.06(4H,                                                                     270.2 (dec.)          34                                                                                ##STR32##     3379, 1616, 1608, 1381, 1233, 1166.                                                          3.98(2H, s), 7.47˜7.90(4H,                                                                     290.0 (dec.)          35                                                                                ##STR33##     1740, 1376, 1166                                                                             2.88(3H, s), 4.53(2H, s), 8.10(2H, s),                                        8.80(1H, s), 11.59(1H,                                                                               258.0 (dec.)          36                                                                                ##STR34##     3328, 1740, 1390, 1159                                                                       4.60(2H, s), 7.33˜7.78(5H, m),                                          11.85(1H, bs)          222.8 (dec.)          37                                                                                ##STR35##     1741, 1380, 1162                                                                             4.54(2H, s), 7.52˜7.63(2H, m),                                          8.10˜8.29 (2H, m), 8.86(1H, s),                                         11.58(1H, bs)          218.3˜226.7     38                                                                                ##STR36##     1739, 1377, 1165                                                                             4.49(2H, s), 7.50˜8.28(4H, m),                                          11.68(1H, bs)          237.8˜243.0     39                                                                                ##STR37##     1746, 1682, 1363, 1158                                                                       2.59(3H, s), 4.07(3H, s), 4.51(2H, s),                                        7.57˜8.13(3H, m), 11.55(1H,                                                                    263.0 (dec.)          40                                                                                ##STR38##     1735, 1691, 1387, 1173                                                                       2.63(3H, s), 4.10(3H, s), 4.54(2H, s),                                        7.36(1H, d, J=8.6Hz), 8.02(2H, m),                                            11.56(1H, bs)          242.3˜244.1     41                                                                                ##STR39##     1803, 1746, 1716, 1377, 1164                                                                 4.51(2H, s), 6.64(1H, d, J=9.9Hz),                                            7.62(1H, d, J=8.9Hz), 8.11˜8.46(3H,                                      m), 11.60(1H, bs)     262.8˜267.8     42                                                                                ##STR40##     1741, 1371, 1169                                                                             2.87(3H, s), 4.55(2H, s), 7.95˜8.51                                     (3H, m), 11.59(1H, bs) 245.2˜246.3     43                                                                                ##STR41##     1741, 1362, 1168                                                                             4.55(2H, s), 8.12(2H, s), 8.82(1H, s),                                        12.67(1H, bs)                                44                                                                                ##STR42##     3098, 1743, 1385, 1364, 1186, 1162, 1067                                                     4.52(2H, s), 7.99˜8.66(3H, m),                                          9.45(1H, d, J=1.0Hz), 11.59(1H,                                                                      203 (dec.)            45                                                                                ##STR43##     3095, 1741, 1373, 1360, 1177, 1150                                                           4.56(2H, s), 7.51˜8.51(5H, m),                                          11.59(1H, bs)          238.7˜244.9     46                                                                                ##STR44##     1729, 1362, 1166                                                                             4.54(2H, s), 7.66˜8.59(5H, m),                                          11.56(1H, bs)          268.4˜271.4     47                                                                                ##STR45##     3174, 1735, 1390, 1170                                                                       4.61(2H, s), 7.57˜7.74(2H, m),                                          7.95˜8.34(3H, m), 11.55(1H,                                                                    242.9˜244.3     48                                                                                ##STR46##     1800, 1742, 1396, 1162                                                                       4.43(2H, s), 6.78(1H, m), 7.45(1H, d,                                         J=3.6Hz), 8.09(1H, m), 11.72(1H,                                                                     243.0˜244.2     49                                                                                ##STR47##     3227, 1735, 1365, 1183, 1171                                                                 4.51(2H, s), 7.55(1H, s), 11.76(1H,                                                                  251.2˜251.3     50                                                                                ##STR48##     1742, 1375, 1174                                                                             4.53(2H, s), 7.71(1H, m), 8.40(1H, m),                                        8.89˜9.14(2H, m), 11.65(1H,                                                                    175.5 (dec.)          51 CH.sub.3       1744, 1384, 1359, 1164, 1153                                                                 3.35(3H, s), 4.33(2H, s),                                                                            196.2˜198.3                                      11.65(1H, bs)                                52                                                                                ##STR49##     1749, 1727, 1371, 1170                                                                       4.55(2H, s), 7.38˜8.16(9H, m),                                          11.63(1H, bs)          261.0˜261.5     __________________________________________________________________________

EXAMPLE 53 Preparation of 1-(4,5-diphenythiophen-2-ylsulfonyl)hydantoinStep 1 Preparation of 4,5-diphenylthiophen-2-ylsulfonyl chloride

Starting from 2,3-diphenyhhiophen, the objective compound was obtainedin a manner similar to Step 1 of Example 26.

IR (KBr, cm⁻¹): 1382, 1172, 1038, 698, 583

NMR (CDCl₃, ppm): 7.27-7.33 (10H, m), 7.89 (1H, s)

Step 2 Preparation of N-(4,5-diphenyhhiophen-2-ylsulfonyl)glycine ethylester

To a suspension of 4,5-diphenyhhiophen-2-ylsulfonyl chloride (36.5 g)and glycine ethyl ester hydrochloride (30.4 g) in dichloromethane (320ml) was added slowly triethylamine (3.03 mi) under ice-cooling, and themixture was stirred for 160 minutes at room temperature. Water (200 ml)was added to the resultant solution, and extracted with dichloromethane.The organic layer was washed successively with 1N hydrochloric acid,water and saturated aqueous NaCl solution, and dried over anhydrousmagnesium sulfate. Dichloromethane was removed in vacuo, and the residuewas reprecipitated from ethyl acetate and hexane to give 41.1 g of theobjective compound.

Melting point: 151.2°-152.7° C.

IR (KBr, cm⁻¹): 3266, 1734, 1354, 1231, 1215, 1164, 1127

NMR (DMSO-d₆, ppm): 1.12 (3H, t, J=7.1 Hz), 3.88 (2H, d, J=6.3 Hz), 4.04(2H, q, J=7.1 Hz), 6.84-7.44 (10H, m), 7.67 (1H, s), 8.57 (1H, t, J=6.3Hz)

Step 3 Preparation of N-(4,5-diphenylthiophen-2-ylsuifonyl)glycine

A solution of sodium hydroxide (12.4 g) in water (73 ml) was added to asolution of the product obtained in Step 2 (41.4 g) in tetrahydrofuran(730 ml), and the mixture was stirred for 25 minutes at 60° C. Afterremoving the solvent, water (300 ml) was added to the residue, and theresultant solution was acidified with concentrated hydrochloric acid toa pH 1 under ice-cooling. The acidified solution was extracted thricewith ethyl acetate (800 ml), the organic layer was washed with water,then with maturated aqueous NaCl solution, and dried over anhydroussodium sulfate. Ethyl acetate was removed in vacuo, the residue wasreprecipitated from ethyl acetate and hexane to give 37.6 g of theobjective compound.

Melting point: 172.2°-174.4° C.

IR (KBr, cm⁻¹): 3268, 1736, 1353, 1159

NMR (DMSO-d₆, ppm): 3.78 (2H, d, J=5.9 Hz), 7.12-7.42 (10H, m), 7.67(1H, s), 8.39 (1H, t, J=5.9 Hz), 12.78 (1H, bs)

Step 4 Preparation of1-(4,5-diphenylthiophen-2-ylsulfonyl-2-thiohydantoin

Starting from the product obtained in Step 3, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 213.2°-215.4° C.

IR (KBr, cm⁻¹): 1752, 1446, 1376, 1168, 1083

NMR (DMSO-d₆, ppm): 4.77 (2H, s), 7.32-7.46 (10H, m), 8.12 (1H, s),12.73 (1H, bs)

Step 5 Preparation of 1-(4,5-diphenylthiophen-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 4, the objective compound wasobtained in a manner similar to Step 4 of Example 26.

Melting point: 242.5°-243.9° C.

IR (KBr, cm⁻¹): 1737, 1386, 1165

NMR (DMSO-d₆, ppm): 4.53 (2H, s), 7.32-7.45 (10H, m), 8.00 (1H, s),11.72 (1H, bs)

Compounds of Example 54 and 55 prepared in a manner similar to Example53 are summarized in the following table 5 together with correspondingIR and NMR data and melting points.

                                      TABLE 5                                     __________________________________________________________________________     ##STR50##                                                                    Ex.                                                     M.P.                  No.                                                                              Q                   IR(KBr, cm.sup.-1)                                                                          NMR(DMSO-d.sub.6, ppm)                                                                           (°C.)          __________________________________________________________________________    54                                                                                ##STR51##          1721, 1367, 1349, 1172, 1161                                                                0.96˜2.40(10H, m),                                                      3.30˜3.69(1H, m), 4.31(2H, s),                                          11.61(1H, bs)      154.9˜156.7     55                                                                                ##STR52##          1735, 1725, 1359, 1163                                                                      0.69˜1.98(15H, m),                                                      3.42˜3.59(2H, m), 4.33(2H, s),                                          11.64(1H, bs)      141.3˜143.2     __________________________________________________________________________

EXAMPLE 56 Preparation of1-(5-nitrobcnzo[b]thlophen-2-ylsulfonyl)hydantoin. (compound 42) Step 1Preparation of 5-nitrobenzo[b]thiophen-2-ylsulfonyl chloride

To a solution of 5-nitrobenzo[b]thiophen (60 g) in anhydroustetrahydrofuran (2 l) was added dropwise a solution of lithiumdiisopropylamide comprising 1.6M n-butyllithium in hexane (240 ml) anddiisopropylamine (57.8 ml) and anhydrous ether (170 ml) with stirring at-70° C. under nitrogen atmosphere. After stirring for 30 minutes intothe solution was bubbled sulfur dioxide for 90 minutes with stirring at-70° C. Then the solution was stirred for 1 hour at room temperature andthe formed precipitate was separated by filtration to give lithium5-nitrobenzo[b]-thiophen-2-ylsulfinate. Into the suspension of theproduct in concentrated hydrochloric acid (500 ml) and water (125 ml)was bubbled chlorine gas for 3 hours with sufficiently stirring at below0° C. After stirring for 1 hour at room temperature, the resultingsuspension was extracted with dichloromethane (400 ml×2) and the organiclayer was washed with successive water and saturated aqueous NaClsolution. After drying over anhydrous sodium sulfate, dichloromethanewas removed in vacuo, and the residue was purified by silica gel columnchromatography to give 21 g of the objective compound.

IR (KBr, cm⁻¹): 1602. 1519, 1378, 1340, 1172

NMR (CDCl₃, ppm): 8.10 (1H, d, J=8.9 Hz), 8.31 (1H, s), 8.46 (1H, dd,J=8.9, 2.0 Hz), 8.90 (1H, d, J=2.0 Hz)

Step 2 Preparation of N-(5-nitrobenzo[b]thiophen-2-ylsulfonyl)glycine

Starting from 5-nitrobenzo[b]thiophen-2-ylsulfonyl chloride, theobjective compound was obtained in a manner similar to Step 1 or Example1.

Melting point: 187.2°-194.8° C.

IR (KBr, cm⁻¹): 3325, 1734, 1530, 1377, 1351, 1159

NMR (DMSO-d₆, ppm): 3.76 (2H, d, J=5.9 Hz), 8.22 (1H, s), 8.32-8.91 (4H,m), 12.72 (1H, bs)

Step 3 Preparation of1-(5-nitrobenzo[b]thiophen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 217.4° C. (decomposition)

IR (KBr, cm⁻¹): 1762, 1521, 1470. 1389, 1347, 1248, 1173, 1087

NMR (DMSO-d₆, ppm): 4.73 (2H, s), 8.25-9.09 (4H, m), 12.78 (1H, bs)

Step 4 Preparation of 1-(5-nitrobenzo[b]thiophen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Step 3 (1.66 g) and 50% (w/v)nitric acid (35 ml) was heated with stirring for 6 hours at 60° C, andthe resultant solution was poured into ice-water (150 ml). The formedprecipitate was separated by filtration and washed with acetone to give0.47 g of the objective compound.

Melting point: 282.4° C. (decomposition)

IR (KBr, cm⁻¹): 3100, 1737, 1522, 1385, 1349, 1176

NMR (DMSO-d₆, ppm): 4.47 (2H, s), 8.22-9.05 (4H, m), 11.70 (1H, bs)

EXAMPLE 57 Preparation of1-(5-cyanobenzo[b]thiophen-2-ylsulfonyl)hydantoin Step 1 Preparation of5-cyanobenzo[b]thiophen-2-ylsulfonyl chloride.

Starting from benzo[b]thiophen-5-ylcarbonitrile, the objective compoundwas obtained in a manner similar to Step 1 of Example 56.

IR (KBr, cm⁻¹): 2236, 1500, 1376, 1171, 577

NMR (DMSO-₆, ppm): 7.56 (1H, s), 7.70 (1H, dd, J=8.9, 2.0 Hz), 8.15 (1H,d, J=8.9 Hz), 8.37 (1H, d, J=2.0 Hz)

Step 2 Preparation of N-(5-cyanobenzo[b]thiophen-2-ylsulfonyl)glycine

Starting from 5-cyanobenzo[b]thiophen-2-ylsulfonyl chloride, theobjective compound was obtained in a manner similar to Step 1 of Example1.

IR (KBr, cm⁻¹): 3289, 2235. 1714, 1350, 1153

NMR (DMSO-d₆, ppm): 3.75 (2H, d, J=5.6 Hz), 7.87 (1H, dd, J=8.6, 1.3Hz), 8.06 (1H, s), 8.34 (1H, d, J=8.6 Hz), 8.56 (1H, d, J=1.3 Hz), 8.70(1H, t, J=5.6 Hz), 12.69 (1H, bs)

Step 3 Preparation of1-(5-cyanobenzo[b]thiophen-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

IR (KBr, cm⁻¹): 2231, 1762, 1451, 1243, 1173, 1077

NMR (DMSO-d₆, ppm): 4.73 (2H, s), 7.95 (1H, dd, J=8.6, 1.7 Hz), 8.41(1H, d, J=8.6 Hz), 8.53 (1H, s), 8.63 (1H, d, J=1.7 Hz), 12.72 (1H, bs)

Step 4 Preparation of 1-(5-cyanobenzo[b]thiophen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Step 3 (0.39 g) and 50% (w/v)nitric acid (8.2 mi) was heated with stirring for 5 minutes at 80° C.,then for 30 minutes at room temperature, and the resultant solution waspoured into ice-water (35 ml). The formed precipitate was separated byfiltration and washed with acetone (100 ml) to give 0.11 g of theobjective compound.

Melting point: 276.3° C. (decomposition)

IR (KBr, cm⁻¹): 3100, 2231, 1740, 1386, 1172

NMR DMSO-d₆, ppm) 4.47 (2H, s), 7.95 (1H, dd, J=8.6, 1.7 Hz), 8.41 (1H,s), 8.42 (1H, d, J=8.6 Hz), 8.65 (1H, d, J=1.7 Hz), 11.75(1H, bs)

EXAMPLE 58 Preparation of1-(5-carboxybenzo[b]thiophen-2-ylsulfonyl)hydantoin

To the suspension of the product obtained in Step 4 of Example 57 (0.1g) in water (1.5 ml) was added slowly concentrated sulfuric acid (1.5ml) and acetic acid (1.5 ml) under ice-cooling, and the mixture wasstirred under reflux for 2 hours. After cooling to room temperature, theformed precipitate was separated by filtration and washed with acetone(20 ml). The washings were concentrated in vacuo, and the residue wastriturated with ether (2 ml) to give 0.02 g of the objective compound.

Melting point: >300° C.

IR (KBr, cm⁻¹): 1743, 1690, 1380. 1163

NMR (DMSO-d₆, ppm): 4.46 (2H, s), 8.07 (1H, dd, J=8.6, 1.7 Hz), 8.28(1H, d, J=8.6 Hz), 8.48 (1H, s), 8.69(1H, d, J=1.7 Hz)

EXAMPLE 59 Preparation of 1-(indol-2-ylsulfonyl)hydantoin Step 1Preparation of 1-benzenesulfonylindol-2-ylsulfonyl chloride

To a solution of lithium diisopropylamide comprising 1.6M n-butyllithiumin hexane (422 ml), diisopropylamine (101 ml) and anhydrous ether (260ml) was added dropwise, solution of 1-benzenesulfonylindole (150 g) inanhydorous ether (2060 ml) with stirring at 0° C. After stirring for 15mlnutes at 0° C., the solution was poured into sulfuryl chloride (125ml) at -50° C. and stirred for 2 hours. The resulting solution waspoured into ice-water (2.51) and stirred sufficiently and then theorganic layer was extracted. The aqueous layer was extracted with ethylacetate (2l) and the combined organic layer was washed with successivewater and saturated aqueous NaCl solution. After drying over anhydroussodium sulfate, ether and ethyl acetate were removed in vacuo and theresidue was triturated with ether to give 146 g of the objectivecompound.

IR (KBr, cm⁻¹): 1513, 1387, 1378, 1245, 1188

NMR (CDCl₃, ppm): 7.29-8.36 (10 H, m)

Step 2 Preparation of

N-(1-benzenesulfonylindol-2-ylsulfonyl)glycine ethyl ester

Starting from 1-benzenesulfonylindol-2-ylsulfonyl chloride, theobjective compound was obtained in a manner similar to Step 2 of Example53.

IR (KBr, cm⁻¹): 3335, 1746, 1346, 1338, 1171

NMR(DMSO-d₆, ppm): 1.11 (3H, t, J=7.3 Hz),3.94 (2H, d, J=5.6 Hz), 4.06(2H, q, J=7.3 Hz), 6.38 (1H, t. J=5.6 Hz), 7.14-8.32 (10H, m)

Step 3 Preparation of N-(indol-2-ylsulfonyl)glycine

A solution of sodium hydroxide (1.6 g) in water (7 ml) was added to asolution of the product obtained in Step 2 (4.22 g) in tetrahydrofuran(70 ml) at room temperature, and the mixture was stirred for 5 mlnutesat 65°-75° C. After removing tetrahydofuran in vacuo, a solution ofsodium hydroxide (0.4 g) in water (23 ml) was added to the residue, andthe mixture was stirred for 5 hours at 65°-75° C. After cooling to roomtemperature, the resultant solution was washed with ether, acidifiedwith 6N hydrochloric acid to a pH 1 under ice-cooling, and extractedwith ethyl acetate (15 ml×3). The organic layer was washed with waterand saturated aqueous NaCl solution, and dried over anhydrous sodiumsulfate. Ethyl acetate was removed in vacuo, and the residue wastriturated with ethyl acetate and hexane to give 1.66 g of the objectivecompound.

Melting point: 170.2°-171.9° C.

IR (KBr, cm⁻¹): 3328, 1707, 1340, 1155, 1145

NMR (DMSO-d₆, ppm): 3.73 (2H, d, J=6.3 Hz), 6.94-7.70 (5H, m), 8.05 (1H,t, J=6.3 Hz), 11.90 (1H, bs), 12.67 (1H, bs)

Step 4 Preparation of 1-(indol-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 3, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 209.2°-210.4° C.

IR (KBr, cm⁻¹): 3131, 3103, 1755, 1473, 1367, 1249, 1197, 1165, 1147,1079

NMR (DMSO-d₆, ppm): 4.81 (2H, s), 7.08-7.78 (5H, m), 12.33 (1H, bs),12.66 (1H, bs)

Step 5 Preparation of 1-(indol-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 4, the objective compound wasobtained in a manner similar to Step 4 of Example 26.

Melting point: 287.1° C. (decomposition)

IR (KBr, cm⁻¹): 3290, 1787, 1725, 1389, 1365, 1156

NMR (DMSO₆, ppm): 4.67 (2H, s), 7.29-7.58 (5H, m), 11.67 (1H, bs), 12.63(1H, bs)

EXAMPLE 60 Preparation of 1-(2-carboxychromon-6-ylsulfonyl)hydantoinStep 1 Preparation of 2-methoxycarbonylchromon-6-ylsulfonyl chloride

To a solution of methyl 6-aminochromon-2-carboxylate (20 g) in water(132 ml) was added concentrated sulfuric acid (26.4 m') and then sodiumnitrite (9.0 g) at 0° C. After stirring for 30 mlnutes, to the solutionwas added sulfur dioxide (19.7 ml), acetic acid (112 ml), concentratedhydrochloric acid (26 ml) and copper (II) chloride dihydrate (11.2 g)and then the mixture was stirred for 15 mlnutes. The formed precipitatewas separated by filtration and dissolved in dichloromethane (600 ml)and the resulting solution was washed with saturated aqueous NaClsolution. After drying over anhydrous sodium sulfate, dichloromethanewas removed in vacuo to give 22 g of the objective compound.

IR (KBr, cm⁻¹): 1744, 1661, 1381, 1287, 1174. 600

NMR (DMSO-d₆, ppm): 6.96 (1H, s), 7.70 (1H, d, J=8.6 Hz). 8.04 (1H, dd,J=8.6, 2.0 Hz), 8.25 (1H, d, J=2.0 Hz)

Step 2 Preparation of N-(2-methoxycarbonylchromon-6-ylsulfonyl)glycine

To a suspension of 2-methoxycarbonylchromon-6-ylsulfonyl chloride (20.0g) in acetone (600 ml) was added slowly a solution of glycine (6.15 g),sodium hydroxide (3.28 g) and sodium bicarbonate (6.11 g) in water (300ml), and the mixture was stirred for 85 mlnutes at room temperature.After adjusting a pH of the resultant solution to ca. 6 with 6 Nhydochloric acid, acetone was removed in vacuo, and insoluble matterswere filtered off. The filtrate was acidified with 2 N hydrochloric acidto a pH 1 under ice-cooling. The acidified solution was extracted withethyl acetate (350 ml×3), the organic layer was washed with water, thensaturated aqueous NaCl solution. and dried over anhydrous sodiumsulfate. Ethyl acetate was removed in vacuo, the residue was purified bysilica-gel column chromatography to give 5.45 g of the objectivecompound.

Melting point: 210.6°-212.8° C.

IR (KBr, cm⁻¹): 3327, 1746, 1716, 1659, 1288, 1266, 1165

NMR (DMSO-d₆, ppm): 3.67 (2H, d, J=5.9 Hz), 3.96 (3H, s), 7.04 (1H, s),7.89-8.42 (4H, m)

Step 3 Preparation of1-(2-methoxycarbonylchromon-6-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 2, the objective compound wasobtained in a manner similar to Step 2 of Example 1.

Melting point: 217.4° C. (decomposition)

IR (KBr, cm⁻¹): 1746. 1660, 1443, 1374, 1282, 1260, 1174

NMR (DMSO-d₆, ppm): 3.96 (3H, s), 4.84 (2H, s), 7.07 (1H, s), 7.9-8.71(3H, m), 12.68 (1H, bs)

Step 4 Preparation of 1-(2-methoxycarbonylchromon-6-ylsulfonyl)hydantoin

Starting from the product obtained in Step 3, the objective compound wasobtained in a manner similar to Step 4 of Example 26.

Melting point: >300° C.

IR (KBr, cm⁻¹): 1751, 1741, 1664, 1617, 1375. 1177,

NMR (DMSO-d₆, ppm): 3.96 (3H, s), 4.52 (2H, s) 7.07 (1H, s), 7.98-8.64(3H, m)

Step 5 Preparation of 1-(2-carboxychromon-6-ylsulfonyl)hydantoin

A solution of the product obtained in Step 4 (2.27 g) in a saturatedaqueous sodium bicarbonate solution (22.7 ml) was stirred for 2 hours at40° C. The resultant solution was washed with ethyl acetate andacidified with 2 N hydrochloric acid to a pH 1 under ice-cooling, andthe formed precipitate was separated by filtration to give 0.82 g of theobjective compound.

Melting point: 279.3° C. (decomposition)

IR, (KBr, cm⁻¹): 3220, 1751, 1663, 1376, 1172

NMR (DMSO-d₆, ppm): 4.54 (2H, s), 7.02 (1H, s), 7.95-8.61 (3H, m), 11.63(1H, bs)

EXAMPLE 61 Preparation of 1-(benzothiazol-2-ylsulfonyl)hydantoin(compound 22) Step 1 Preparation of 2-benzylthiobertzothiazole

To a solution of 2-benzothiazolthlol (250 g) in N,N-dimethylformamide(1l) was added triethylamine (208 ml) under ice-cooling and dropwise asolution of benzyl bromide (178 ml) in N,N-dimethylformamide (300 ml)and the mixture was stirred for 40 minutes. The resulting solution waspoured into water (101) and the formed precipitate was separated byfiltration and dissolved in dichloromethane (3 l). After drying overanhydorpus magnesium sulfate, dichloromethane was removed in vacuo togive 378 g of the objective compound.

Step 2 Preparation of benzothlazol-2-ylsulfonyl chloride

Into a mixture of 2-benzylthiobenzothiazole (100 g) and acetic acid (500ml) in water (500 ml) was bubbled chlorine gas for 1.5 hours withstirring at -1:5° C. The resulting solution was poured into icewater(1.5 l), the formed precipitate was separated by filtration to give 90.9g of the objective compound.

Step 3 Preparation of N-(benzothiazol-2-ylsulfonyl)glycinamide

To a suspension of glycinamide hydrochloride (43 g) in dioxane (1l) wasadded benzothiazol-2-ylsulfonyl chloride (90.9 g) under ice-cooling, anda pH of the mixture was adjusted to 8 with saturated aqueous sodiumcarbonate solution. After stirring for 1.5 hours, the resultant solutionwas concentrated in vacuo. Water (1.5l) was added to the residue, andthe solution was acidified with concentrated hydrochloric acid to pH 2.The formed precipitate was separated by filtration to give 59.8 g of theobjective compound.

Melting point: 179.7°-181.8° C.

IR (KBr, cm⁻¹): 3426, 1682. 1345, 1165

NMR (DMSO-d₆, ppm): 3.73 (2H, s), 7.08 (1H, bs), 7.50 (1H, bs).7.52-8.29 (4H, m), 8.80 (1H, bs)

Step 4 Preparation ofN-(benzothiazol-2-ylsulfonyl)N-methoxycarbonylglycinamide

To a solution of the product obtained in Step 3 (102.3 g) inN,N-dimethylformamide 0.2l) was added slowly 60% sodium hydride (16.7 g)under ice-cooling, and the mixture was stirred for 1 hour at roomtemperature. Methyl chlorocarbonate (35.8 g) was added to theabove-mentioned mixture followed by stirring for 1 hour at roomtemperature. After removing the solvent, water (3.5 l) was added to theresidue, and the formed precipitate was separated by filtration to give60.5 g of the objective compound.

Melting point: 153.1° C. (decomposition)

IR (KBr, cm⁻¹): 3459, 3346, 1737, 1689, 1386, 1343, 1250, 1171

NMR (DMSO-d₆, ppm): 3.10 (3H, s), 4.51 (2H, s), 7.30 (1H, bs), 7.60-7.76(3H, m), 8.20-8.39 (2H, m)

Step 5 Preparation of 1-(benzothiazol-2-ylsulfonyl)hydantoin

To a solution of the product obtained in Step 4 (20.0 g) inN,N-dimethylformamide (200 ml) added slowly 60% sodium hydride (2.67 g),and the mixture was stirred for 13.5 hours at 70° C. After removing thesolvent, water (1) was added to the residue, and the solution wasextracted with ethyl acetate (1.5 l). The organic layer was washed withsaturated aqueous NaCl solution, and dried over anhydrous sodiumsulfate. Ethyl acetate was removed in vacuo, and the residue was washedwith acetone-chloroform (100 ml+200 ml) to give 2.12 g of the objectivecompound.

Melting point: 260.4°-261 9° C.

IR (KBr, cm⁻¹): 3200, 3105, 1739, 1393, 1355, 1173

NMR (DMSO-d₆, ppm): 4.55 (2H, s), 7.61-7.81 (2H, m), 8.18-8.40 (2H, m).11.88 (1H, bs)

EXAMPLE 62 Preparation of 1-(benzo[c]thiophen-1-ylsulfonyl)hydantoinStep 1 Preparation of N² -(benzo[c]thiophen-1-ylsulfonyl)glycinamide

To a solution ot benzo[c]thiophen (5.5 g) in anhydrous ether (50 ml) wasadded 1.6 M solution of n-butyllithium in hexane (52.2 ml) at -20° C.under nitrogen atmosphere. After stirring for 1 hour, into the solutionwas bubbled sulfur dioxide for 1 hour with stirring at -20° C. Ether wasremoved in vacuo and the residue was suspended in isopropanol (200 ml)and water (200 ml). To the suspension was added N-chlorosuccinimide (6.5g) at 0° C. After stirring for 30 minutes at 0° C., N-chlorosuccinimide(1.63 g) was added and the mixture was stirred for additional 1 hour.The resulting solution was extracted with dichloromethane (1 l×2) andthe organic layer was washed with successive water and saturated aqueousNaCl solution. After drying over anhydrous sodium sulfate,dichloromcthane was removed in vacuo under cooling. Using this residueand glycinamide hydrochloride, the objective compound was obtained in amanner similar to Step 3 of Example 50.

NMR (DMSO-d₆, ppm): 3.40 (2H, d, J=6.9 Hz), 7.06-8.22 (5H, m), 8.49 (1H,s)

Step 2 Preparation of N-(benzo[c]thiophen-1-ylsulfonyl)-N2-methoxycarbonylglycinamide

To a solution of the product obtained in Step 1 (0.45 g) inN,N-dimethylformamide (5 ml) was added slowly (60% sodium hydride (75mg) under ice-oooling, and the mixture was stirred for 30 minutes atroom temperature. Methyl chloroformate (0.14 ml) was added to theabove-mentioned mixture followed by stirring for 20 minutes at roomtemperature. 60% sodium hydride (75 mg) was added to the solution, andthe mixture was stirred for 1.5 hours at room temperature, then 15minutes at 70° C. After cooling to room temperature, water (20 ml) wasadded to the resultant mixture and this aqueous solution was extractedwith ethyl acetate (20 ml×3). The organic layer was washed with water,then saturated aqueous NaCl solution. After drying over anhydrousmagnesium sulfate, ethyl acetate was removed in vacuo and the residuewas purified by silica-gel columun chromatography to give 0.18 g of theobjective compound.

NMR (CDCl₃, ppm): 3.74 (3H, s), 4.24 (2H, d, J=5.3 Hz), 5.92 (1H, t,J=5.3 Hz), 7.17-8.31 (6H, m)

Step 3 Preparation of 1-(bennzo[c]thiophen-1-ylsulfonyl)hydantoin

To a solution of the product obtained in Step 2 (0.18 g) inN,N-dimethylformamide (3 ml) added slowly 60% sodium hydride (48 mg),and the mixture was stirred for 2.5 hours at 70° C. After removing thesolvent, ice water (20 ml) was added to the residue, and pH of thesolution was adjusted to 4 with 1 N hydrochloric acid. The resultantsolution was extracted with ethyl acetate (20 ml×3), and the organiclayer was washed with saturated aqueous NaCl solution, and dried overanhydrous magnesium sulfate. Ethyl acetate was removed in vacuo, and theresidue was triturated with dichloromethane to give 0.03 g of theobjective compound.

Melting point: 223.6°-226.9° C.

IR (KBr, cm⁻¹): 1736, 1378, 1185, 1162, 1152

NMR (DMSO-d₆, ppm): 4.51 (2H, s), 7.20-8.16 (4H, m)8.82 (1H, s), 11.54(1H, bs)

Intermediate compounds of Example 6 to 25, 28 to 52, 54 and 55 aresummarized to the following table 6 and 7 together with corresponding IRand NMR data and melting points.

                                      TABLE 6                                     __________________________________________________________________________    QSO.sub.2 NHCH.sub.2 CO.sub.2 H                                               Ex. No.                                                                            Q                   IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    M.P. (°C.)                __________________________________________________________________________          ##STR53##          3345, 1710, 1315, 1140                                                                3.69(2H, d), 7.61˜8.37(6H, m),                                          8.49(1H, s) 174.5˜ 182.1               7                                                                                   ##STR54##                  3.70(2H, d, J=5.9Hz), 7.72˜8.50(7H,                                      m)         185.2˜ 186.4               8                                                                                   ##STR55##                  3.44(2H, s), 7.52˜8.60(7H,                                                          >300                             9                                                                                   ##STR56##          3350, 1715, 1320, 1145                                                                3.55(2H, d, J=5.8Hz), 7.51˜8.30(6H,                                      m), 8.48(1H, s)                                                                          158.8˜ 165.7               10                                                                                  ##STR57##                  3.73(2H, s), 7.51˜8.53(7H,                                                          247.8˜ 254.7               11                                                                                  ##STR58##                  3.69(2H, d, J=6.0Hz), 7.58˜8.71(7H,                                      m)         157.8˜ 162.1               12                                                                                  ##STR59##          3345, 1715 1330, 1165                                                                 3.78(2H, d, J=5.9Hz), 7.61˜8.22(5H,                                      m), 8.42(1H, s), 8.64(1H,                                                                210.0˜ 214.4               13                                                                                  ##STR60##          3350, 1715, 1320, 1145                                                                3.48(2H, s), 7.52˜8.48(7H,                                                          257.2˜ 265.7               14                                                                                  ##STR61##                  2.98(3H, s), 3.62(2H, d, J=5.9Hz),                                            7.52˜8.35(7H, m)                                                                    179.0˜ 182.7               15                                                                                  ##STR62##                  2.79(3H, s), 3.73(2H, d, J=6.1Hz),                                            7.43˜8.35(6H, m), 8.53(1H,                                                          155.5˜ 160.5               16                                                                                  ##STR63##                  2.49(3H, s), 3.40(2H, s), 7.35˜8.39                                     (7H, m)     225.7˜ 230.6               17                                                                                  ##STR64##                  2.49(3H, s), 3.65(2H, s), 7.35˜8.45                                     (7H, m)     147.4˜ 152.0               18                                                                                  ##STR65##          3340, 1710, 1325, 1155                                                                3.62(2H, d, J=6.0Hz), 3.91(3H, s),                                            7.19˜8.15(6H, m), 8.31(1H,                                                          161.4˜ 163.6               19                                                                                  ##STR66##                  3.78(2H, d, J=5.9Hz), 7.67˜8.45(7H,                                      m)         163.5˜ 168.5               20                                                                                  ##STR67##                  3.62(2H, s), 7.05˜8.50(7H,                                                          109.0˜ 109.5               21                                                                                  ##STR68##                  3.55(2H, s), 3.93(6H, s), 7.35˜7.98                                     (5H, m), 8.24(1H, s)                                                                      212.6˜ 217.1               22                                                                                  ##STR69##          3280, 2230, 1760, 1155                                                                3.71(2H, d, J=6.0Hz), 7.87˜8.65(6H,                                      m)         231.9˜ 234.9               23                                                                                  ##STR70##          3260, 2240, 1740, 1155                                                                3.69(2H, d, J=6.0Hz), 7.82˜8.73(7H,                                      m)         186.2˜ 192.0               24                                                                                  ##STR71##                  3.72(2H, d, J=5.7Hz), 8.09˜8.68(4H,                                      m)         258.8˜ 261.5               25                                                                                  ##STR72##                  3.06(6H, s), 3.55(2H, d, J=6.0Hz),                                            6.91˜8.21(7H, m)                                                                    148.0˜ 152.0               28                                                                                  ##STR73##          3348, 1710, 1518, 1334, 1142                                                          3.68(2H, d, J=6.3Hz), 7.78˜8.89(7H,                                      m), 12.63(1H, bs)                                                                        224.9˜ 227.7               29                                                                                  ##STR74##          3290, 1709, 1342, 1156                                                                3.73(2H, d, J=5.9Hz), 7.31˜8.22(4H,                                      m), 8.59(1H, t, J=5.9Hz), 12.72(1H,                                                      162.7˜ 164.2               30                                                                                  ##STR75##          3295, 1709, 1343, 1156                                                                3.73(2H, d, J=5.9Hz), 7.49˜8.17(4H,                                      m), 8.59(1H, t, J=5.9Hz), 12.54(1H,                                                      186.9˜ 189.1               31                                                                                  ##STR76##          3337, 1716, 1342, 1257, 1162                                                          3.83(2H, d, J=6.3Hz), 7.52˜8.24(4H,                                      m), 8.87(1H, t, J=6.3Hz), 12.63(1H,                                                      156.6˜ 161.0               32                                                                                  ##STR77##          3255, 1710, 1356, 1248, 1160                                                          3.78(2H, d, J=5.9Hz), 7.44˜8.13(4H,                                      m), 8.66(1H, t, J=5.9Hz), 12.68(1H,                                                      197.0˜ 199.2               33                                                                                  ##STR78##          3334, 1717, 1437, 1352, 1241, 1152                                                    3.78(2H, s), 7.49(1H, s), 7.68(2H, s),                                        8.00(1H, s), 8.83(1H, bs)                                                                 192.4˜ 194.1               34                                                                                  ##STR79##          3377, 1718, 1358, 1247, 1157                                                           3.76(2H, s), 7.44˜7.89(4H,                                                         191.5˜ 193.8               35                                                                                  ##STR80##          3290, 1720, 1340, 1170                                                                2.86(3H, s), 3.63(2H, d, J=6.3Hz),                                            7.79˜8.54(4H, m), 12.48(1H,                                                         237.7 (dec.)                     36                                                                                  ##STR81##          3068, 1718, 1617, 1349, 1155                                                          3.78(2H, s), 7.25˜7.70(4H,                                                          133.5˜ 135.9               37                                                                                  ##STR82##          3318, 1724, 1339, 1241, 1152                                                          3.64(2H, d, J=5.9Hz), 7.36˜7.60(2H,                                      m), 7.97˜8.45(4H, m)                  38                                                                                  ##STR83##          3094, 1721, 1358, 1164                                                                3.82(2H, s), 7.43˜8.17(4H, m),                                          9.09(1H, bs), 12.51(1H,                                                                   212.5˜ 214.4               39                                                                                  ##STR84##          3290, 1733, 1655, 1331, 1158                                                          2.58(3H, s), 3.61(2H, d, J=5.9Hz),                                            4.03(3H, s), 7.49˜8.17(4H, m),                                          12.50(1H, bs)                                                                             215.0˜ 217.6               41                                                                                  ##STR85##          3265, 1748, 1711, 1316, 1205, 1154                                                    3.65(2H, d, J=5.9Hz), 6.62(1H, d,                                             J=9.9Hz), 7.57(1H, d, J=8.6Hz), 7.92.abou                                     t.8.25(4H, m), 12.69(1H,                                                                  235.0 (dec)                      42                                                                                  ##STR86##          3302, 1727, 1330, 1216, 1154                                                          2.85(3H, s), 3.63(2H, d, J=5.9Hz),                                            7.73˜8.29(4H, m)                                                                    257.2 (dec.)                     43                                                                                  ##STR87##          3213, 1718, 1317, 1255, 1164, 1153                                                    3.64(2H, d, J=5.6Hz), 7.78˜8.38(4H,                                      m)         243.5˜ 245.3               44                                                                                  ##STR88##          3271, 1742, 1316, 1149                                                                3.64(2H, d, J=6.3Hz), 7.90˜8.63(4H,                                      m), 9.38(1H, s), 12.57(1H,                                                               165.3˜ 168.5               45                                                                                  ##STR89##          3097, 1741, 1316, 1209, 1148                                                          3.57(2H, d, J=5.9(Hz), 7.39˜8.33(6H                                     , m)                                         46                                                                                  ##STR90##          3186, 1765, 1751, 1732, 1335, 1145                                                    3.60(2H, d, J=6.3Hz), 7.61˜8.35(6H,                                      m), 12.58(1H, bs)                           47                                                                                  ##STR91##          3282, 1727, 1309, 1161, 1137                                                          3.65(2H, d, J=5.9Hz), 7.47˜8.18(5H,                                      m), 8.33(1H, t, J=5.9Hz), 12.64(1H, bs)     48                                                                                  ##STR92##          3307, 1725, 1340, 1329, 1157                                                          3.66(2H, d, J=6.3Hz), 6.58˜7.90(3H,                                      m), 8.38(1H, t, J=6.3(Hz), 12.63(1H,                                         bs)                                          49                                                                                  ##STR93##          3358, 1728,  1348, 1236, 1166                                                         3.76(2H, d, J=5.9Hz), 7.28(1H, s),                                            8.45(1H, t, J=5.9Hz), 12.76(1H, bs)          50                                                                                  ##STR94##          3236, 1701, 1341, 1174                                                                3.70(2H, d, J=5.9Hz), 7.54˜8.24(2H,                                      m), 8.33(1H, t, J=5.9Hz), 8.76˜8.9                                     6(2H, m), 12.70(1H, bs)                                                                   220.4˜ 223.8               51   CH.sub.3            3258, 1711,                                                                           2.92(3H, s),                                                                              168.0˜                                              1320, 1247,                                                                           3.72(2H, d, J=5.9Hz),                                                                     171.0                                                     1148    7.39(1H, t, J=5.9Hz),                                                         12.71(1H, bs)                                52                                                                                  ##STR95##          3348, 1714, 1323, 1152                                                                3.62(2H, d, J=6.3Hz), 7.44˜7.87(9H,                                      m), 8.06(1H, t, J=6.3Hz)                    54                                                                                  ##STR96##          3308, 1714, 1319, 1147, 1126                                                          1.18˜2.06(10H, m), 2.64˜3.19(                                     1H, m), 3.69(2H, d, J=6.0Hz), 7.33(1H,                                        t, J=6.0Hz) 96.0˜ 100.9                55                                                                                  ##STR97##          3314, 3256, 2921, 1716, 1313, 1141                                                     ##STR98##                                   __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR99##                                                                    Ex. No.                                                                            Q                   IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    H.P. (°C.)                __________________________________________________________________________          ##STR100##         3130, 1785, 1760, 1165                                                                4.90(2H, s), 7.69˜8.45(5H, m),                                          8.88(1H, s) 212.9˜ 222.8               7                                                                                   ##STR101##                 4.88(2H, s), 7.74˜8.83(6H,                                                          250.1 (dec.)                     8                                                                                   ##STR102##                 4.89(2H, s), 7.59˜8.43(5H, m),                                          8.70˜8.96(1H, m)                                                                    231.4 (dec.)                     9                                                                                   ##STR103##         3150, 1795, 1770, 1170                                                                4.93(2H, s), 7.61˜8.35(5H, m),                                          8.89(1H, s) 211.4˜ 221.9               10                                                                                  ##STR104##                 4.88(2H, s), 7.68˜8.39(5H, m),                                          8.80(1H, s) 227.8 (dec.)                     11                                                                                  ##STR105##                 4.89(2H, s), 7.60˜8.29(5H, m),                                          8.69˜8.87(1H, m)                                                                    190.5 (dec.)                     12                                                                                  ##STR106##         3270, 1795, 1770, 1170                                                                4.94(2H, s), 7.65˜8.51(5H, m),                                          8.99(1H, s) 248.5˜ 255.7               13                                                                                  ##STR107##         3120, 1785, 1755, 1165                                                                4.85(2H, s), 7.70˜8.40(5H, m),                                          8.67˜8.84(1H, m)                                                                    198.5˜ 209.5               14                                                                                  ##STR108##                 2.97(3H, s), 4.86(2H, s), 7.55˜8.47                                     (6H, m)     243.9 (dec.)                     15                                                                                  ##STR109##                 2.64(3H, s), 4.80(2H, s), 7.47˜8.26                                     (5H, m), 8.81(1H, s)                                                                      242.0˜ 244.7               16                                                                                  ##STR110##                 2.53(3H, s), 4.91(2H, s), 7.45˜                                         8.68(5H, m), 8.70(1H, s)                                                                  234.8˜ 237.6               17                                                                                  ##STR111##                 2.52(3H, s), 4.71(2H, s), 7.29˜8.03                                     (5H, m), 8.58˜8.69(1H,                                                              232.7˜ 238.2               18                                                                                  ##STR112##         3250, 1790, 1755, 1165                                                                3.94(3H, s), 4.85(2H, s), 7.23˜7.51                                     (2H, m), 7.87˜8.17(3H, m),                                              8.67(1H, s) 236.4 (dec.)                     19                                                                                  ##STR113##                 4.82(2H, s), 7.67˜8.33(6H,                                                          248.0 (dec.)                     20                                                                                  ##STR114##                 4.86(2H, s), 7.23˜8.61(6H,                                                          177.1˜ 184.7               21                                                                                  ##STR115##                 3.95(6H, s), 4.86(2H, s), 7.45˜7.97                                     (4H, m), 8.45˜8.59(1H,                                                              260.7 (dec.)                     22                                                                                  ##STR116##         2230, 1760, 1350, 1170                                                                 4.88(2H, s), 7.88˜8.55(4H, m),                                         8.73˜9.00(1H, m)                                                                    223.9 (dec.)                     23                                                                                  ##STR117##         2225, 1760, 1350, 1170                                                                4.88(2H, s), 7.81˜8.46(4H, m),                                          8.64˜8.92(2H, m), 12.60(1H,                                                         131.0˜ 135.8               24                                                                                  ##STR118##                 4.86(2H, s), 8.46˜8.99(3H, m),                                          12.60(1H, bs)                                                                             270.0 (dec.)                     25                                                                                  ##STR119##                 3.10(6H, s), 4.82(2H, s), 6.93˜8.03                                     (5H, m), 8.47(1H, s)                                                                      256.4 (dec.)                     28                                                                                  ##STR120##         1793, 1764, 1527, 1345 1172                                                           4.85(2H, s), 7.80˜9.24(6H, m),                                          12.67(1H, bs)                                                                             229.6 (dec.)                     29                                                                                  ##STR121##         1757, 1391, 1253, 1176                                                                4.74(2H, s), 7.41˜8.50(4H, m),                                          12.76(1H, bs)                                                                             240.4˜ 242.5               30                                                                                  ##STR122##         1761, 1468, 1385, 1249, 1170                                                          4.73(2H, s), 7.50˜8.46(4H, m),                                          12.77(1H, bs)                                                                             208.3 (dec.)                     31                                                                                  ##STR123##         1784, 1756, 1462, 1374, 1245, 1173                                                    4.92(2H, s), 7.50˜8.34(4H, m),                                          12.95(1H, bs)                                                                             275.3 (dec.)                     32                                                                                  ##STR124##         1746, 1467, 1382, 1257, 1171                                                          4.79(2H, s), 7.53˜8.40(4H, m),                                          12.76(1H, bs)                                                                             221.2˜ 224.6               33                                                                                  ##STR125##         1751, 1436, 1392, 1237, 1165                                                          4.74(2H, s), 7.65˜8.10(4H, m),                                          12.72(1H, bs)                                                                             186.7˜ 187.7               34                                                                                  ##STR126##         1750, 1458, 1394, 1164                                                                4.74(2H, s), 7.50˜8.07(4H, m),                                          12.83(1H, bs)                                                                             213.9 (dec.)                     35                                                                                  ##STR127##         1748, 1378, 1245, 1175                                                                2.88(3H, s), 4.83(2H, s), 8.13(2H, s),                                        8.87(1H, s), 12.62(1H,                                                                    240.4 (dec.)                     36                                                                                  ##STR128##         1785, 1758, 1449, 1388, 1255, 1185, 1160                                              4.84(2H, s), 7.26˜7.86(4H, m),                                          12.94(1H, bs)                                37                                                                                  ##STR129##         3111, 1793, 1762, 1463, 1374, 1174                                                    4.87(2H, s); 7.47˜7.68(2H, m),                                          8.04˜8.28(2H, m), 9.01(1H, s),                                          12.64(1H, bs)                                38                                                                                  ##STR130##         1757, 1386, 1167                                                                      4.83(2H, s), 7.50˜8.34(4H, m),                                          12.77(1H, bs)                                                                             203.1 (dec.)                     39                                                                                  ##STR131##         1764, 1680, 1475, 1361, 1319, 1162                                                    2.59(3H, s), 4.08(3H, s), 4.77(2H, s),                                        7.50˜8.28(3H, m), 12.51(1H,                                                         244.0 (dec.)                     40                                                                                  ##STR132##         1746, 1671, 1362, 1305, 1186, 1167                                                    2.63(3H, s), 4.10(3H, s), 4.85(2H, s),                                        7.32(1H, d, J=8.9Hz), 7.95(1H, s),                                            8.14(1H, d, J=8.9Hz), 12.54(1H, bs)          41                                                                                  ##STR133##         1745, 1467, 1385, 1360, 1170                                                          4.81(2H, s), 6.65(1H, d, J=9.6Hz),                                            7.62(1H, d, J=8.9Hz), 8.04˜8.58(3H,                                      m), 12.66(1H, bs)                                                                        230.2 (dec.)                     42                                                                                  ##STR134##         1762, 1613, 1370, 1241, 1174                                                          2.87(3H, s), 4.85(2H, s), 7.92˜8.64                                     (3H, m), 12.61(1H, bs)                                                                    226.0 (dec.)                     43                                                                                  ##STR135##         1755, 1459, 1380, 1169                                                                2.96(3H, s), 4.89(2H, s), 8.41(2H, s),                                        9.06(1H, s), 12.60(1H,                                                                    222.7 (dec.)                     44                                                                                  ##STR136##         1759, 1459, 1370, 1243, 1189, 1162                                                    4.83(2H, s), 7.99˜8.75(3H, m),                                          9.46(1H, s), 12.64(1H,                                                                    264.0 (dec.)                     45                                                                                  ##STR137##         1745, 1476, 1362, 1267, 1199, 1170                                                    4.90(2H, s), 7.46˜8.55(5H, m),                                          12.63(1H, bs)                                46                                                                                  ##STR138##         1755, 1474, 1364, 1256, 1200, 1169                                                    4.84(2H, s), 7.50˜8.73(5H, m),                                          12.58(1H, bs)                                47                                                                                  ##STR139##         1743, 1459, 1390, 1346, 1172                                                          4.91(2H, s), 7.55˜8.31(5H, m),                                          12.71(1H, bs)                                48                                                                                  ##STR140##         1753, 1431, 1381, 1191, 1166                                                           ##STR141##                                  49                                                                                  ##STR142##         1795, 1758, 1452, 1432, 1374, 1177                                                    4.77(2H, s), 7.65(1H, s), 12.85(1H, bs)      50                                                                                  ##STR143##         1788, 1755, 1378, 1263, 1173                                                          4.82(2H, s), 7.62˜9.22(4H, m),                                          12.69(1H, bs)                                                                             221.0 (dec.)                     51   CH.sub.3            1745, 1470,                                                                           3.57(3H, s),                                                                              213.4˜                                              1424, 1361,                                                                           4.52(2H, s),                                                                              216.0                                                     1165    12.70(1H, bs)                                52                                                                                  ##STR144##         1743, 1456, 1374, 1171                                                                4.84(2H, s), 7.47˜8.23(9H, m),                                          12.65(1H, bs)                                54                                                                                  ##STR145##         1791, 1757, 1735, 1453, 1353, 1236, 1169                                              1.24˜2.23(10H, m), 3.90˜4.32(                                     1H, m), 4.50(2H, s), 12.70(1H, bs)           55                                                                                  ##STR146##         1748, 1735,  1454, 1363, 1235,                                                         ##STR147##                                  __________________________________________________________________________

Now, typical but non-limiting examples of formulations of the compoundof this invention will be shown below.

Formulation A (Capsules)

Compound 13, 300 g of weight, 685 g of lactose and 15 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous.The mixture was then filled in No. 1 hard gelatin capsule at 200 mg eachto obtain capsule preparation.

Formulation B (Tablets)

Compound 15, 300 g of weight, 550 g of lactose, 120 g of potato starch.15 g of polyvinyl alcohol and 15 g of magnesium stearate were weighed.The weighed amount of compound 15, lactose and potato starch were mixeduntil accomplishing homogeneity. Then aqueous solution ofpolyvinylalcohol was added to the mixture and granulated by wet process.The granules were then dried, mixed with magnesium stearate and pressedinto tablets, each weighing 200 mg.

Formulation C (Powder)

Compound 8, 200 g of weight, 790 g of lactose and 10 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous toobtain 20% powder preparation.

Formulation D (Capsules)

Compound 16, 300 g of weight, 685 g of lactose and 15 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous.The mixture was then filled in No. 1 hard gelatin capsule at 200 mg eachto obtain capsule preparation.

Formulation E (Tablets)

Compound 19, 300 g of weight, 550 g of lactose, 120 g of potato starch,15 g of polyvinyl alcohol and 15 g of magnesium stearate were weighed.The weighed amount of compound 19, lactose and potato starch were mixeduntil accomplishing homogeneity. Then aqueous solution ofpolyvinylalcohol was added to the mixture and granulated by wet process.The granules were then dried, mixed with magnesium stearate and pressedinto tablets, each weighing 200 mg.

Compounds of Example 63 to 77 prepared in a manner similar to Example 26are summarized in the following table 8 together with corresponding IRand NMR data and melting points.

                                      TABLE 8                                     __________________________________________________________________________     ##STR148##                                                                   Ex.                                      M.P.                                 No.                                                                              Q                 IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                         __________________________________________________________________________    63                                                                                ##STR149##       1800, 1750, 1739, 1381, 1160                                                          4.46(2H, s), 7.57(1H, dd, J=8.6, 1.7Hz),                                      8.11(1H, d, J=8.6Hz), 8.33(2H,                                                            249.1˜ 251.3                   64                                                                                ##STR150##       3096, 1786, 1734, 1376, 1166                                                          4.48(2H, s), 7.50˜7.81(1H, m),                                          8.11(1H, dd, J=6.6, 1.3Hz), 8.44(1H, s),                                      11.74(1H, bs)                                                                             285.0 (dec.)                         65                                                                                ##STR151##       3210, 1809, 1728, 1392 1160                                                           1.46(6H, d, J=7.3Hz), 3.96˜4.28(1H,                                     m),  4.52(2H, s), 7.48˜7.67(2H, m),                                     8.07˜8.32(2H, m), 11.76(1H,                                                         174.1˜ 176.6                   66                                                                                ##STR152##       1733, 1379, 1180                                                                      4.53(2H, s), 7.66˜8.38(4H, m),                                          11.95(1H, bs)                                                                             243.2 (dec.)                         67                                                                                ##STR153##       3160, 1805, 1725, 1379, 1183                                                          4.70(2H, s), 7.57˜8.28(4H, m),                                          11.86(1H, bs)                                                                             288.0˜ 289.5                   68                                                                                ##STR154##       1804, 1744, 1378, 1178                                                                 ##STR155## 196.0˜ 197.5                   69                                                                                ##STR156##       3300, 1779, 1729, 1382, 1173, 1167                                                    4.44(2H, s), 7.95(1H, s), 11.75(1H,                                                        283.2 (dec.)                        70                                                                                ##STR157##       3270, 1807, 1742, 1389, 1169                                                          4.45(2H, s), 7.72(1H, d, J=1.6Hz), 7.96(1H,                                   d, J=1.0Hz), 8.07(1H, dd, J=1.6, 1.0Hz),                                      11.78(1H, bs)                                                                             290.8 (dec.)                         71                                                                                ##STR158##       3220, 1800, 1783, 1397, 1176, 1154                                                    4.52(2H, s), 7.43˜7.91(4H,                                                          265.7˜ 267.9                   72                                                                                ##STR159##       3080, 1805, 1725, 1378, 1187, 1177                                                    4.62(2H, s), 8.40(1H, s), 11.84(1H,                                                       278.0 (dec.)                         73                                                                                ##STR160##       3209, 3177, 1812, 1726, 1490, 1379, 1305, 1176,                                       4.69(2H, s), 7.51˜7.90(3H, m),                                          11.90(1H, bs)                                                                             286.0 (dec.)                         74                                                                                ##STR161##       3210, 1806, 1735, 1364, 1158.                                                         1.62˜1.92(4H, m), 2.46˜2.91(4H,                                   m), 4.40(2H, s), 7.60(1H, s), 11.61(1H,                                                   248.3˜ 249.5                   75                                                                                ##STR162##       1810, 1793, 1396, 1177                                                                4.34(2H, s), 7.43˜7.88(9H, rc),                                         11.76(1H, bs)                                                                             220.4 (dec.)                         76                                                                                ##STR163##       3230, 1742, 1389, 1183                                                                4.47(2H, s), 7.53˜8.13(4H, m),                                          11.72(1H, bs)                                                                             256.0˜ 258.0                   77                                                                                ##STR164##       3103, 1805, 1787, 1729, 1534, 1426, 1383, 1366,                                       4.41(2H, s), 7.21(1H, d, J=5.6Hz), 8.12(1H,                                   dd, J=5.6, 4.3Hz), 11.73(1H,                                                              238.2˜ 240.9                   __________________________________________________________________________

Compounds of Example 78 to 81 prepared in a manner similar to Example 53are summarized in the following table 9 together with corresponding IRand NMR data and melting points.

                                      TABLE 9                                     __________________________________________________________________________     ##STR165##                                                                   Ex.                                  M.P.                                     No.                                                                              Q             IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                             __________________________________________________________________________    78                                                                                ##STR166##   3170, 1787, 1732, 1365, 1171                                                          4.61(2H, s), 7.50˜7.61(2H,                                              m), 8.04˜8.26(2H, m), 11.72(1H,                                                     215.0˜ 219.0                       79                                                                                ##STR167##   3214, 1778, 1725, 1528, 1439, 1346                                                    4.53(2H, s), 7.49˜7.68(2H,                                              m), 8.03˜8.17(2H, m), 11.87(1H,                                                     221.1˜ 223.2                       80                                                                                ##STR168##   1810, 1742, 1391, 1165, 1139                                                          4.48(2H, s), 7.28˜7.89(4H, m), 11.61(1H,                                bs)         277.0 (dec.)                             81                                                                                ##STR169##   3190, 3040, 1795, 1750, 1372, 1170                                                    2.19(3H, s), 2.54(3H, s), 4.41(2H, s), 11.61(1H,                              bs), 12.73(1H, bs)                                                                        >300                                     __________________________________________________________________________

Compounds of Example 82 and 83 prepared in a manner similar to Example61 are summarized in the following table 10 together with correspondingIR and NMR data and melting points.

                                      TABLE 10                                    __________________________________________________________________________     ##STR170##                                                                   Ex.                                   M.P.                                    No.                                                                              Q              IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                            __________________________________________________________________________    82                                                                                ##STR171##    3200, 1801, 1724, 1374, 1180                                                          2.47(3H, s), 4.77(2H, s), 7.60˜7.76(2H,                                 m), 8.09˜8.25(2H, m), 11.83(1H,                                                     213.2˜ 222.0                      83                                                                                ##STR172##    3240, 1990, 1728, 1371, 1163                                                          4.18(3H, s), 4.55(2H, s), 7.55˜7.66(2H,                                 m), 8.06˜8.14(2H, m), 11.70(1H,                                                     239.7˜ 241.3                      __________________________________________________________________________

EXAMPLE 84 Preparation of1-(3-carboxymethylbenzo[b]thiophen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Step 4 of Example 68 (0.85 g) and60% (w/v) nitric acid (9 ml) was heated with stirring for 140 minutes at70° C. After cooling to room temperature, the formed precipitate wasseparated by filtration and washed with ether to give 0.21 g of theobjective compound.

Melting point: 224.4° C. (decomposition)

IR (KBr cm⁻¹): 3220, 1800, 1736, 1718, 1374, 1170

NMR (DMSO-d₆, ppm): 4.32 (2H, s), 4.47 (2H, s), 7.55-7.65 (2H, m),7.99-8.19 (2H, m), 11.71 (1H, bs)

EXAMPLE 85 Preparation of1-(3-methylsulfinylbenzo[b]thiophen-2-ylsulfonyl)hydamtoin

To a suspension of the product obtained in Example 82 (0.65 g) indichloromethanc (26 ml) was added m-chloroperbenzoic acid (0.41 g) andthe mixture was stirred for 1.5 hours at room temperature. The resultingsolution was concentrated in vacuo and the residue was washed with ether(30 ml). The residue was purified by silica gel column chromatography togive 0.48 g of the objective compound.

Melting point: 215.0°-221.0° C.

IR (KBr, cm⁻¹): 1792, 1743, 1379, 1180

NMR (DMSO-d₆, ppm): 3.10 (3H, s), 4.57 (2H, S), 7.51-8.89 (4H, m), 11.81(1H, bs)

EXAMPLE 86 Preparation of1-(3-methylsulfonylbenzo[b]thiophen-2-ylsulfonyl)hydantoin (compound 32)

To a suspension of the product obtained in Example 82 (0.65 g) in ethylacetate (26 ml) was added m-chloroperbenzoic acid (0.82 g) and themixture was stirred under reflux for 1.5 hours. Additionalm-chloroperbenzoic acid (0.16 g) was added and the mixture was stirredunder reflux for more 1.5 hours. The resulting solution was concentratedin vacuo and the residue was washed with successive methanol and etherto give 0.40 g of the objective compound.

Melting point: 224.0°-245.0° C.

IR (KBr, cm⁻¹): 1771. 1372, 1324, 1179

NMR (DMSO-d₆, ppm): 3.47 (3H, s), 4.63 (2H, s), 7.66-8.59 (4H, m), 11.90(1H, bs)

EXAMPLE 87 Preparation of1-(3-cyanobenzo[b]thiophen-2-ylsulfonyl)hydantoin (compound 33)

To a mixture of the product obtained in Example 67 (11.3 g) and copper(I) cyanide (4.1 g) was added pyridine (42 ml). After stirring at 70° C.for 17 hours, a solution of Iron (IIl) chloride hexahydrate (15.7 g) inconcentrated hydrochloric acid (3.9 ml) and water (23.6 ml) was addedslowly to the solution and the resultant mixture was heated withstirring for 5 minutes at 50° C. The formed precipitate was separated byfiltration and the filtrate was extracted with ethyl acetate (300 ml)and the organic layer was washed with successive water and saturatedaqueous NaCl solution and dried over anhydrous sodium sulfate. Abovementioned precipitate was extracted by ethanol and this ethanol solutionwas combined with above mentioned organic layer. The resulting solutionwas concentrated in vacuo and purified by silica gel columnchromatography to give 1.21 g of the objective compound.

Melting point: 238.9°-242.5° C.

IR (KBr, cm⁻¹): 2233, 1807, 1746, 1736, 1388, 1167

NMR (DMSO-d₆, ppm): 4.51 (2H, s), 7.70-8.47 (4H, m), 11.83 (1H, bs)

EXAMPLE 88 Preparation of1-(3-hydroxybenzo[b]thlophen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Example 83 (2.5 g), acetic acid (7ml) and 47% hydrobromic acid (8.9 ml) was stirred for 1 hour at roomtemperature and heated for 1 hour at 40° C., for more 1 hour at 50° C.To the mixture was added additional acetic acid (7 ml) and 47%hydrobromic acid (8.9 ml) and heated with stirring for 1 hour at 60° C.,for 2 hours at 80° C. The resulting solution was poured into water (300ml) and extracted with ethyl acetate (1.2 l). After drying overanhydrous magnesium sulfate, ethyl acetate was removed in vacuo and theresidue was dissolved in acetone (800 ml). After decoloring withactivated charcoal, acetone was removed in vacuo and the residue waswashed with successive ethyl acetate and ether to give 1.13 g of theobjective compound.

Melting point: 171.8° C. (decomposition)

IR (KBr, cm⁻¹): 3260, 1800, 1735, 1358, 1185, 1164

NMR (DMSO-d₆, ppm): 4.60 (2H, s), 7.46-8.19 (4H, m), 11.70 (1H, bs)

EXAMPLE 89 Preparation of1-(3-carbamoylbenzo[b]thiophen-2-ylsulfonyl)hydantoin

A mixture of the product obtained in Example 87 (0.84 g) and 80% (v/v)sulfuric acid (16.3 ml) was heated with stirring for 8 hours at 70° C.and the resulting solution was poured into ice-water (200 ml). Theformed precipitate was separated by filtration and washed withsuccessive water, ethanol and acetone to give 0.16 g of the objectivecompound.

Melting point: 241.9°-244.6° C.

IR (KBr, cm⁻¹): 3412, 3197, 1795, 1741, 1376, 1162

NMR (DMSO-d₆, ppm): 4.51 (2H, s), 7.56-8.44 (6H, m), 11.73 (1H, bs)

EXAMPLE 90 Preparation of1-(3-carboxybenzo[b]thiophen-2-ylsulfonyl)hydantoin

To a suspension of the product obtained in Example 89 (0.60 g) inconcentrated sulfuric acid (18 ml) was added sodium nitrite (2.4 g)under cooling at -15° C. and the resulting suspension was stirred for 15minutes at -15° C., for 30 minutes at 0° C. and for 50 minutes at roomtemperaiure. To the mixture was added additional sodium nitrite (1.2 g)and stirred for 30 minutes at room temperature. After adjusting a pH ofthe resulting solution to ca. 9 with 0.1 M sodium bicarbonate, theresulting solution was washed with ethyl acetate and acidified withconcentrated hydrochloric acid to a pH about 2 and extracted with ethylacetate (200 ml). The organic layer was washed with successive water andsaturated aqueous NaCl solution. After drying over anhydrous sodiumsulfate, ethyl acetate was removed in vacuo and the residue was purifiedby silica gel column chromatography to give 0.18 g of the objectivecompound.

Melting point: 228.8°-235.1° C.

IR (KBr, cm⁻¹): 3450, 1739, 1735, 1380, 1175

NMR (DMSO-d₆, ppm): 4.73 (2H, s), 7.45-8.17 (4H, m), 11.76 (1H, bs)

EXAMPLE 91 Preparation of1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin (compound 47) Step 1Preparation of 3-chlorobenzo[b]furan-2-yl-sulfonyl chloride

To a solution of 3-chlorobenzo[b]furan (11.4 g) in anhydrous ether (62ml) was added dropwise 1.5M lithium diisopropylamidemono(tetrahydrofuran) in hexane (62 ml) under nitrogen atmosphere at-70° C. After stirring for 30 minutes, into the solution was bubbledsulfur dioxide for 1 hour with stirring at -60° C. Then the solution wasstirred for 1 hour at room temperature and the formed precipitate wasseparated by filtration to give lithium3-chlorobenzo[b]furan-2-sulfidate. To the suspension of the product indichloromethane (250 ml) was added N-chlorosuccinimide (11.0 g) at -50°C. and stirred for 3 hours. After stirring for 2 hours underice-cooling. insoluble matters were filtered off. Dichloromethane wasremoved in vacuo and the residue was purified by silica gel columnchromatography to give 8.8 g of the objective compound.

Melting point: 60.6°-68.2° C.

IR (KBr, cm⁻¹): 1538, 1402, 1232, 1183, 1151, 1039

NMR (CDCl₃, ppm): 7.40-7.98 (4H, m)

Step 2 Preparation of N-(3-chlorobenzo[b]furan-2-ylsulfonyl)glycineethyl ester

To a suspension of 3-chlorobenzo[b]furan-2-ylsulfonyl chloride (8.6 g)and glycine ethyl ester hydrochloride (9.6 g) in dichloromethane (83 ml)was added slowly triethylamine (10.4 ml) under ice-cooling and then theresulting mixture was stirred for 30 minutes at room temperature. Water(150 ml) was added to the resultant solution and acidified with 1Mhydrochloric acid to a pH 2, and the acidified solution was extractedwith ethyl acetate (300 ml). After drying over anhydrous magnesiumsulfate, ethyl acetate was removed in vacuo to give 10.2 g of theobjective compound.

Melting point: 104.5°-110.8° C.

IR (KBr, cm⁻¹): 3203, 1736, 1365, 1230, 1149

NMR (DMSO-d₆, ppm): 1.01 (3H, t, J=7.1 Hz), 3.89 (2H, q, J=7.1 Hz), 3.94(2H, s), 7.50-7.73 (4H, m), 9.12 (1H, bs)

Step 3 Preparation of N-(3-chlorobenzo[b]furan-2-ylsulfonyl)glycine

To a solution of N-(3-chlorobenzo[b]furan-2-ylsulfonyl)glycine ethylester (10.2 g) in tetrahydrofuran (160 ml) was added dropwise a solutionof sodium hydroxide (4.9 g) in water (16 ml) under ice-cooling and theresulting solution was stirred for 1 hour. After stirring for 30 minutesat room temperature, tetrahydrofuran was removed in vacuo. Water (200ml) was added to the residue and then acidified with concentratedhydrochloric acid under ice-cooling to a pH1 and the acidified solutionwas extracted with ethyl acetate (500 ml). The organic layer was washedwith saturated aqueous NaCl solution. After drying over anhydrousmagnesium sulfate, ethyl acetate was removed in vacuo to give 9.2 g ofthe objective compound.

Melting point: 163.8°-167.9° C.

IR (KBr, cm⁻¹ : 3236, 1709, 1369, 1232, 1153

NMR (DMSO-d₆, ppm): 3.84 (2H, d, J=5.9 Hz), 7.38-7.81 (4H, m), 9.03 (1H,t, J=5.9 Hz), 12.67 (1H, bs)

Step 4 Preparation of1-(3-chlorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

To a mixture of N-(3-chlorobenzo[b]furan-2-ylsulfonyl)glycine (9.2 g),ammonium thiocyanate (5.32 g) and acetic anhydride (18 ml) was addeddropwise pyridine (6.68 ml) under ice-cooling and resulting mixture wasstirred for 30 minutes at room temperature, for 30 minutes at 40° C. andfor 2 hours at 70°-80° C. After coolivg to room temperature, theresulting solution was poured into ice-water (300 ml) and the formedprecipitate was separated by filtration and washed with water-ethanol togive 6.73 g of the objective compound.

Melting point: 195.4°-204.7° C.

IR (KBr, cm⁻¹): 3158, 1758, 1393, 1234, 1179

NMR (DMSO-d₆, ppm): 4.83 (2H, s), 7.56-7.90 (4H, m)

Step 5 Preparation of 1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin

To a suspension of iodine monochloride (5.3 ml) in 1M hydrochloric acid(160 ml) was added1-(3-chlorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin (6.7 g) and thendichloromethane (200 ml) dropwise. The mixture was stirred for 1.5 hoursunder ice-cooling and for 1.5 hours at room temperature. After addingsaturated aqueous sodium sulfite solution, the reaction mixture wasextracted with ethyl acetate (600 ml). The organic layer was washed withsuccessive saturated aqueous sodium sulfite solution and saturatedaqueous NaCl solution. After drying over anhydrous magnesium sulfate,ethyl acetate was removed in vacuo and the residue was washed withsuccessive ether and ether-ethyl acetate to give 3.15 g of the objectivecompound.

Melting point: 246.6°-256.8° C.

IR (KBr, cm⁻¹): 3226, 1744, 1397, 1363, 1174, 1156

NMR (DMSO-d₆, ppm): 4.51 (2H, s), 7.54-7.89 (4H, m), 11.81 (1H, bs)

EXAMPLE 92 Preparation of 1-(4-bromobenzo[b]furan-2-ylsulfonyl)hydantoinStep 1 Preparation of (3-bromophenyloxy)acetaldehyde dimethyl acetal

To a suspension of 60% sodium hydride. (60 g) in N,N-dimethylformamide(1.4 l) was added dropwise 3-bromophenol (260 g) under ice-cooling.After stirring for 10 minutes, to the solution was added dropwisebromoacetaldehyde dimethyl acetai (318 g) and the mixture was heatedwith stirring for 3 hours at 90° C. After cooling, water was added tothe resulting solution and acidified with 1 M hydrochloric acid and thenextracted with ether (3l). The organic layer was washed with successivewater, saturated aqueous sodium bicarbonate solution and saturatedaqueous NaCl solution. After drying over anhydrous sodium sulfate, etherwas removed in vacuo and the residue was purified by silica gel columnchromatography to give 363.3 g of the objective compound.

IR (neat, cm⁻¹): 2941, 2835, 1615, 1506, 1458

NMR (CDCl₃, ppm): 3.44 (6H, s), 3.96 (2H, d, J=5.0 Hz), 4.69 (1H, t,J=5.0 Hz), 6.77-7.26 (4H, m)

Step 2 Preparation of mixture of 4-bromobenzo[b]furan and6-bromobenzo[b]furan

Under ice-cooling, to phosphoric acid (413.5 ml) was added phosphoruspentoxide (344.2 g) and then chlorobenzene (870 ml). The resultingmixture was heated up to 125° C. To the mixture was added dropwise thesolution of the product obtained in Step 1 (181.7 g) in chlorobenzene(150 ml) at 125° C. and heated with stirring for 1 hour at 12:5° C.After cooling, the resulting mixture was poured into ice-water (2l) andextracted with ether (2l). The organic layer was washed with successivesaturated aqueous sodium bicarbonate solution and saturated aqueous NaClsolution. After drying over anhydrous sodium suifate, ether andchlorobenzene were removed in vacuo and the residue was purified bysilica gel column chromatography to give 116 g of the objectivecompound.

Step 3 Preparation of 4-bromobenzo[b]furan-2-ylsulfonyl chloride

To a solution of the mixture obtained in Step 2 (100 g) in anhydrousether (430 ml) was added dropwise 1.5 M lithium diisopropylamidemono(tetrahydrofuran) in cyclohexane (430 ml) under nitrogen atmosphereat -70° C. After stirring for 30 minutes, into the solution was bubbledsulfur dioxide for 1 hour with stirring at -60° C. Then the solution wasstirred for 3 hours at room temperature and the formed precipitate wasseparated by filtration to give a mixture of lithium4-bromobenzo[b]furan-2-sulfinate and lithium 6bromobenzo[b]furan-2-sulfinate. To the suspension of the products indichloromethane (2l) was added N-chlorosuccinimide (96 g) at -50° C. andstirred for 3 hours under ice-cooling. Insoluble matters were filteredoff and dichloromethane was removed in vacuo and the residue waspurified by silica gel column chromatography to give 14.1 g of theobjective compound.

Melting point: 87.2° C.

IR (KBr, cm⁻¹): 1603, 1578, 1389, 1175, 1165

NMR (CDCl₃, ppm): 7.43-7.67 (4H, m)

Step 4 Preparation of N-(4-bromobenzo[b]furan-2-ylsulfonyl)glycine ethylester

Starting from the product obtained in Step 3 (14.1 g), the objectivecompound (16.8 g) was obtained in a manner similar to Step 2 of Example91.

Melting point: 115.6°-117.3° C.

IR (KBr, cm⁻¹): 3199, 1361, 1221, 1158

NMR (CDCl₃, ppm): 1.18 (3H, t, J=7.1 Hz), 3.97 (2H, d, J=5.3 Hz), 4.09(2H, q, J=7.1 Hz), 5.45 (1H, t, J=5.3 Hz), 7.26-7.58 (4H, m)

Step 5 Preparation of N-(4-bromobenzo[b]furan-2-ylsulfonyl)glycine

Starting from the product obtained in Step 4 (16.8 g), the objectivecompound (14.4 g) was obtained in a manner similar to Step 3 of Example91.

Melting point: 180.0°-182.1° C.

IR (KBr, cm⁻¹): 3253, 1738, 1361, 1262, 1165

NMR (DMSO-d₆, ppm): 3.81 (2H, s), 7.38-7.81 (4H, m), 8.85 (1H, bs)

Step 6 Preparation of1-(4-bromobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

To a suspension of the product obtained in Step 5 (14.4 g) and ammoniumthiocyanate (7.2 g) in acetic anhydride (28 ml) was added dropwisepyridine (9.1 ml) and the mixture was heated with stirring for 2 hoursat 60°-70° C. After cooling to room temperature, the resulting solutionwas poured into ice-water (500 ml) and the formed precipitate wasseparated and washed with ethanol to give 10.7 g of the objectivecompound.

Melting point: 253.3° C.

IR (KBr, cm⁻¹): 3140, 1756, 1391, 1248, 1166

NMR (DMSO-d₆, ppm): 4.77 (2H, s), 7.45-7.88 (3H, m), 7.95 (1H, s), 12.86(1H, bs)

Step 7 Preparation of 1-(4-bromobenzo[b]furan-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 6 (10.7 g), the objectivecompound (4.3 g) was obtained in a manner similar to Step 5 of Example91.

Melting point: 291.7°-293.5° C.

IR (KBr, cm⁻¹): 3240, 1741, 1390, 1355, 1167

NMR (DMSO-d₆, ppm): 4.48 (2H, s), 7.45-7.90 (4H, m), 11.78 (1H, t,s)

EXAMPLE 93 Preparation of1-(7-fluorobcnzo[b]furan-2-ylsulfonyl)hydantoin (compound 48) Step 1Preparation of 7-fluorobenzo[b]furan-2-ylsulfonyl chloride

Starting from 7-fluorobcnzo[b]furan (10.4 g), the objective compound(5.7 g) was obtained in a manner similar to Step 1 of Example 91.

Melting point: 114° C.

IR (KBr, cm⁻¹): 1596, 1546, 1372, 1267, 1178

NMR (CDCl₃, ppm): 7.24-7.69 (4H, m)

Step 2 Preparation of N-(7-fluorobenzo[b]furan-2-ylsulfonyl)glycineethyl ester

Starting from the product obtained in Step 1 (5.7 g), the objectivecompound (6.45 g) was obtained in a manner similar to Step 2 of Example91.

Melting point: 84.5° C.

IR (KBr, cm⁻¹): 3238, 1734, 1376, 1232. 1165

NMR (DMSO-d₆, ppm): 1.03 (3H, t, J=7.1 Hz), 3.89 (2H, d, J=6.3 Hz), 3.92(2H, q. J=7.1 Hz), 7.32-7.66 (4H, m), 9.05 (1H, t, J=6.3 Hz)

Step 3 Preparation of N-(7-fluorobenzo[b]furan-2-ylsulfonyl)glycine

Starting from the product obtained in Step 2 (6.4 g), the objectivecompound (5.42 g) was obtained in a manner similar to Step 3 of Example91.

Melting point: 140.1° C. (decomposition)

IR (KBr, cm⁻¹): 3303, 1734, 1349, 1262, 1160

NMR (DMSO-d₆, ppm): 3.80 (2H, d, J=5.0 Hz), 728-7.66 (4H, m), 8.90 (1H,t, J=5.0 Hz)

Step 4 Preparation of1-(7-fluorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

To a suspension of the product obtained in Step 3 (5.4 g) and ammoniumthiocyanate (3.32 g) in acetic anhydride (12.7 ml) was added dropwisepyridine (4.16 ml) under ice-cooling and nitrogen atmosphere. Themixture was heated with stirring for 2 hours at 70° C. After cooling toroom temperature, the resulting solution was poured into ice-water (200ml) and added small amount of ethanol and the formed precipitate wasseparated and dissolved in ethyl acetate (200 ml) and the solution waswashed with successive water and saturated aqueous NaCl solution. Afterdrying over anhydrous sodium sulfate, ethyl acetate was removed in vacand the residue was washed with ethanol to give 2.83 g of the objectivecompound.

Melting point: 229.9°-232.0° C.

IR (KBr, cm⁻¹): 3258, 1765, 1744, 1448, 1177

NMR (DMSO-d₆, ppm): 4.73 (2H, s), 7.39-7.77 (3H, m), 8.13 (1H, d, J=2.6Hz), 12.83 (1H, bs)

Step 5 Preparation of 1-(7-fluorobenzo[b]furan-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 4 (2.8 g), the objectivecompound (1.1 g) was obtained in a manner similar to Step 5 of Example91.

Melting point: >300° C.

IR (KBr, cm⁻¹): 5381, 1735, 1610, 1383, 1166

NMR (DMSO-d₆, ppm): 3.98 (2H, s), 7.34-7.71 (3H, m), 7.78 (1H, d, J=3.0Hz)

EXAMPLE 94 Preparation of1-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin (compound 44) Step 1Preparation of (3,4-dichlorophenyloxy)acetaldehyde dimethyl acetal

Starting from 3,4-dichlorophenol (200 g), the objective compound (218.8g) was obtained in a manner similar to Step 1 of Example 92.

IR (neat, cm⁻¹): 2940, 2830, 1595, 1475, 1297, 1235

NMR (CDCl₃, ppm): 3.45 (6H, s), 3.96 (2H, d, J=5.3 Hz), 4.69 (1H, t,J=5.3 Hz), 6.78 (1H, dd, J=8.9, 3.0 Hz), 7.02 (1H, d, J=3.0 Hz), 7.31(1H, d, J=8.9 Hz)

Step 2 Preparation of mixture of 4,5-dichlorobenzo[b]furan and5,6-clichlorobenzo[b]furan

Starting from the product obtained in Step 1 (218.8 g), the mixture ofthe objective compounds (102.1 was obtained in a manner similax to Step2 of Example 92.

Step 3 Preparation of 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chlorideand 5,6-dichlorobenzo[b]furan-2-ylsulfonyl chloride

To a solution of the mixture obtained in Step 2 (100 g) in anhydrousether (440 ml) was added dropwise 1.5 M lithium diisopropylnmidemono(tetrahydrofuran) in cyclohexane (440 ml) under nitrogen atmosphereat -70° C. over 1 hour, then into the solution was bubbled sulfurdioxide for 1.5 hours at -70° C. After stirring for 1 hour at roomtemperature, the solvent was removed in vacuo and ether was added to theresidue. The formed precipitate was separated by filtration to give amixture of lithium 4,5-dichlorobenzo[b]furan-2-sulfinate and lithium5,6-dichlorobenzo[b]furan-2-sulfinate. To the suspension of the productsin dichloromethane (1.8 l) was added N-chlorosuccimimide (92.1 g) at-50° C. and stirred for 1.5 hours. At room temperature, insolublematters were filtered off and dichloromethane was removed in vacuo andthe residue was purified by silica gel column chromatography to give17.4 g of 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride and 7.4 g of5,6-dichlorobenzo[b]furan-2-ylsulfonyl chloride, respectively.4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride

Melting point: 114.6° C.

IR (KBr, cm⁻¹, ppm), 1529, 1444, 1401, 1191

NMR (DMSO-d₆, ppm): 6.87 (1H, d, J=1.0 Hz), 7.55 (1H, d, J=8.9 Hz), 7.69(1H, dd, J=8.9, 1.0 Hz) 5,6-dichlorobenzo[b]furan-2-ylsulfonyl chloride

Melting point: 159.8° C.

IR (KBr, cm⁻¹): 1537, 1390, 1163, 1081

NMR (DMSO-d₆, ppm): 6.87 (1H, d, J=1.0 Hz), 7.92 (1H, s), 8.02 (1H, d,J=1.0 Hz)

Step 4 Preparation of N-(4,5-dichlorobenzo[b]furan-2-ylsulfon)glycineethyl ester

Starting from 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride obtainedin Step 3 (17 g), the objective compound (18.2 g) was obtained in amanner similar to Step 2 of Example 91.

Melting point: 155.2°-155.5° C.

IR (KBr, cm-⁻¹): 3199, 1737, 1225, 1160

NMR (CDCl₃, ppm): 1.05 (3H, t, J=7.1 Hz), 3.92 (2H, s), 3.95 (2H, q,J=7.1 Hz), 7.56 (1H, s), 7.78 (2H, s), 9.09 (1H, bs)

Step 5 Preparation of N-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)glycine

Starting from the product obtained in Step 4 (18 g), the objectivecompound (16.2 g) was obtained in a manner similar to Step 3 of Example91.

Melting point: 189.8°-194.7° C.

IR (KBr, cm⁻¹): 3320, 1719, 1366, 1256, 1162

NMR (DMSO-d₆, ppm): 3.83 (2H, d, J=6.3 Hz), 7.56 (1H, s), 7.76 (2H, s),8.97 (1H, t, J=6.3 Hz)

Step 6 Preparation of1-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 5 (16 g), the objectivecompound (7.4 g) was obtained in a manner similar to Step 4 of Example91.

Melting point: 214.6°-217.5° C.

IR (KBr, cm⁻¹): 1793, 1762, 1445, 1167

NMR (DMSO-d₆, ppm): 4.77 (2H, s), 7.85 (2H, s), 8.11 (1H, s), 12.95 (1H,bs)

Step 7 Preparation of1-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin

To a suspension of iodine monochloride (6.3 ml) in 1 M hydrochloric acid(150 ml) were added successively the product obtained in Step 6 (7.3 g)and dropwise dichloromethane (150 ml) over 10 minutes. The mixture wasstirred for 2.5 hours at room temperature. Under ice-cooling, to thesolution was added saturated aqueous sodium sulfite solution and stirredfor a while. The formed precipitate was separated by filtration andwashed with successive water, ethanol and ether to give 4.8 g of theobjective compound.

Melting point: 290.7°-292.0° C. (decomposition)

IR (KBr, cm⁻¹): 3256, 1742, 1391, 1356, 1168

NMR (DMSO-d₆, ppm): 4.47 (2H, s), 7.85 (2H, s), 7.98 (1H, s), 11.80 (1H,bs)

EXAMPLE 95 Preparation of1-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin (compound 45) Step 1Preparation of N-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)glycine ethylester

To a solution of 5,6-dichlorobenzo[b]furan-2-ylsulfonyl chlorideobtained in Step 3 of Example 64 (7.4 g) in dichleromethane (60 ml) wasadded glycine ethyl ester hydrochloride (7.95 g) and added slowlytriethylamine (7.89 ml) under ice-cooling and nitrogen atmosphere. Theresulting solution was poured into water (100 ml) and acidified with 1 Mhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated aqueous NaCl solution and dried over anhydroussodium sulfate. Ethyl acetate was removed in vacuo and the residue waswashed with hexane to give 8.7 g of the objective compound.

Melting point: 132.7°-133.5° C.

IR (KBr, cm⁻¹): 3227, 1735, 1360. 1225, 1158

NMR (DMSO-d₆, ppm): 1.06 (3H, t, J=6.9 Hz), 3.90 (2H, s), 3.95 (2H, q,J=6.9 Hz), 7.52 (1H, s), 8.08 (1H, s), 8.20 (1H, s), 9.05 (1H, b)

Step 2 Preparation of N-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)glycine

Starting from the product obtained in Step 1 (8.6 g), the objectivecompound (7.8 g) was obtained in a manner similar to Step 3 of Example91.

Melting point: 192.6°-201.8° C.

IR (KBr, cm⁻¹): 3367, 1719, 1359, 1248, 1159

NMR (DMSO-d₆, ppm): 3.80 (2H, d, J=5.9 Hz), 7.51 (1H, d, J=1.0 Hz), 8.08(1H, s), 8.19 (1H, d, J=-- 1.0 Hz), 8.92 (1H, t, J=5.9 Hz)

Step 3 Preparation of1-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 2 (7.7 g), the objectivecompound (3.7 g) was obtained in a manner similar to Step 4 of Example91.

Melting point: >246.0° C. (decomposition)

IR (KBr, cm⁻¹): 3100, 1743, 1449, 1246, 1166

NMR (DMSO-d₆, ppm): 4.73 (2H, s), 8.02 (1H, d, J=1.0 Hz), 8.20 (1H, s),8.26 (1H, d, J=1.0 Hz), 12.82 (1H, bs)

Step 4 Preparation of1-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin

Starting from the product obtained in Step 3 (3.7 g), the objectivecompound (2.7 g) was obtained in a manner similar to Step 5 of Example91.

Melting point: >300° C. (decomposition)

IR (KBr, cm⁻¹): 1732, 1389, 1186, 1167

NMR (DMSO-d₆, ppm): 4.31 (2H, s), 7.82 (1H, d, J=0.7 Hz), 8.16 (1H, s),8.27 (1H, d, J=0.7 Hz)

EXAMPLE 96 Preparation of1-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)hydantoin (compound 49)Step 1 Preparation of 2,3-dibromo-2,3-dihydro-7-fluorobenzo[b]furan

To a solution of 7-fluorobenzo[b]furan (16 g) in carbon tetrachloride(40 ml) was added dropwise a solution of bromine (22 g) in carbondisulfide (40 ml) at -30° C. and the solution was stirred for 1 hour. Atroom temperature, the formed precipitate was separated by filtration togive 34.4 g of the objective compound.

IR (KBr, cm⁻¹): 1634, 1601, 1489, 1459, 1279, 1179

NMR (CDCl₃, ppm): 5.74 (1H, d, J=1.3 Hz), 6.93 (1H, s). 7.11-7.35 (3H,m)

Step 2 Preparation of 3-bromo-7-fluorobenzo[b]furan

To a solution of potassium hydroxide (12.7 g) in ethanol (180 ml) wasslowly added the product obtained in Step 1 (34 g) and stirred for 3hours. The resulting solution was neutralized by acetic acid, thenextracted with ether. The organic layer was washed with successive waterand saturated aqueous NaCl solution. After drying over anhydrous sodiumsulfate, ether was removed in vacuo to give 24.1 g of the objectivecompound.

IR (neat, cm⁻¹): 3150, 1636, 1595, 1494, 1434, 1322

NMR (CDCl₃, ppm): 6.98-7.36 (3H, m), 7.68 (1H, s)

Step 3 Preparation of 3-bromo-7-fluorobenzo[b]furan-2-ylsulfonylchloride

Starting from the product obtained in Step 2 (24.1 g), the objectivecompound (12.2 g) was obtained in a manner similar to Step 1 of Example91.

IR (KBr, cm⁻¹): 1602, 1533, 1385, 1168

NMR (DMSO-d₆, ppm): 7.33-7.39 (3H, m)

Step 4 Preparation ofN-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)glycine ethyl ester

Starting from the product obtained in Step 3 (12.2 g), the objectivecompound (10.2 g) was obtained in a manner similar to Step 2 of Example91.

Melting point: 126.2°-126.4 C.

IR (KBr, cm⁻¹): 3200, 1731, 1366, 1237, 1142

NMR (DMSO-d₆, ppm): 1.01 (3H, t, J=7.1 Hz) 3.89 (2H, q, J=7.1 Hz), 3.96(2H, d, J=5.6 Hz), 7.47-7.66 (3H, m), 9.32 (1H, t, J=5.6 Hz)

Step 5 Preparation ofN-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)glycine

Starting from the product obtained in Step 4 (10.2 the objectivecompound (7.25 g) was obtained in a manner similar to Step 3 of Example91.

Melting point: 148.5°-159.6° C.

IR (KBr, cm⁻¹): 3223, 1716, 1373, 1246, 1163

NMR (DMSO-d₆, ppm): 3.86 (2H, s), 7.46-7.58 m), 9.18 (1H, bs)

Step 6 Preparation of1-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin

Starting from the product obtained in Step 5 (7.2 g), the objectivecompound (5.07 g) was obtained in a manner similar to Step 4 of Example91.

Melting point: 224.3°-224.7° C. (decomposition)

IR (KBr, cm⁻¹): 3290, 1793, 1765, 1235, 1141

NMR (DMSO-d ₆, ppm): 4.83 (2H, s), 7.57-7.72 (3H, m), 12.93 (1H, bs)

Step 7 Preparation of1-(3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl)hydantoin

To a suspension of iodine monochloride (3.3 ml) in 1 M hydrochloric acid(110 ml) was added the product obtained in Step 6 (5 g) and dropwisedichloromethane (140 ml). The mixture was stirred for 6 hours at roomtemperature and then additive iodine monochloride (1.7 ml) was added tothe mixture and the resulting mixture was stirred for 1 hour. To theresulting solution was added saturated aqueous sodium sulfite solutionand formed precipitate was separated by filtration. The organic layerwas washed with saturated aqueous NaCl solution and dried over anhydrousmagnesium sulfate. Formed precipitate was suspended in 1 M hydrochloricacid (100 ml) and the suspension was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous NaCl solution and driedover anhydrous magnesium sulfate. Both extracts were combined and thesolvent was removed in vacuo. The resulting residue was washed withsuccessive ethanol and ether to give 1.66 g of the objective compound.

Melting point: 266.6°-270.6° C.

IR (KBr, cm⁻¹): 3160, 1725, 1393, 1184, 1149

NMR (DMSO-d₆, ppm): 4.50 (2H, s), 7.53-7.77 (3H, m), 11.85 (1H, bs)

Compounds of Example 97 to 102 prepared in a manner similar to Example91 are summarized in the following table 11 together with correspondingIR, and NMR data and melting points.

                                      TABLE 11                                    __________________________________________________________________________     ##STR173##                                                                   Ex.                                   M.P.                                    No.                                                                              Q              IR(KBr, cm.sup.-1)                                                                    NMR(DMSO)-d.sub.6, ppm)                                                                   (°C.)                            __________________________________________________________________________    97                                                                                ##STR174##    1732, 1389 1181, 1166                                                                  ##STR175## >297 (dec.)                             98                                                                                ##STR176##    3216, 1734, 1397, 1363, 1175, 1151                                                    4.54(2H, s), 7.51˜7.75(4H, m), 11.82(1H,                                bs)         292 (dec.)                              99                                                                                ##STR177##    1742, 1394, 1183, 1174, 1153                                                           ##STR178## 256.3˜ 258.6 (dec.)               100                                                                               ##STR179##    3262, 1734, 1397, 1352, 1178, 1170                                                    4.44(2H, s), 7.70(1H, d, J=1.0Hz), 7.71(1H, s),                               .22(1H, d, J=1.0Hz)                                                                       >249.2 (dec.)                           101                                                                               ##STR180##    3279, 1744, 1404, 1176, 1148                                                          4.51(2H, s), 7.74(1H, d, J=1.7Hz), 8.16(1H, d,                                J= 1.7Hz), 11.82(1H, bs)                                                                  249.5˜ 251.7                      102                                                                               ##STR181##    3220, 1745, 1407, 1357, 1181, 1152.                                                   4.48(2H, s), 7.58˜7.97(4H,                                                          238.8˜ 240.8                      __________________________________________________________________________

Another intermediate compounds of Example 29 to 39, 41 to 48, 50, 52,54, 63 to 83, 97 to 102 are summarized in the following table 12 to 16together with corresponding IR and NMR data and melting points.

                                      TABLE 12                                    __________________________________________________________________________    QSO.sub.2Cl                                                                   Ex.                                      M.P.                                 No.                                                                              Q                 IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                         __________________________________________________________________________    29                                                                                ##STR182##       1500, 1392, 1216, 1174, 1001                                                          7.12˜8.00(3H, m), 7.43(1H, s)              30                                                                                ##STR183##       1588, 1493, 1169, 1078                                                                7.55(1H, dd, J=8.9, 1.3Hz), 7.85(1H, d,                                       J=8.9Hz), 7.95(1H, d, J=1.3Hz), 8.07(1H, s)*     31                                                                                ##STR184##       1592, 1480, 1391, 1248, 1180                                                          7.37˜8.01(4H, m)                           32                                                                                ##STR185##       1584, 1544, 1493, 1388, 1170, 1007                                                    7.35˜7.95(3H, m), 7.42(1H, s)              33                                                                                ##STR186##        1530, 1372, 1275, 1240, 1160                                                         7.46˜7.92(3H, m), 7.58(1H, s)*             34                                                                                ##STR187##       1531, 1394, 1164, 1080, 809                                                           7.50˜7.76(3H, m), 7.59(1H, s)*             35                                                                                ##STR188##       1508, 1406, 1375, 1320, 1180                                                          2.81(3H, s), 7.74˜8.24(3H, m)              37                                                                                ##STR189##       1423, 1375, 1172                                                                      7.38˜7.72(2H, m), 7.84˜8.01(1H,                                   m), 8.26˜8.46(1H, m), 8.51(1H, s)*         38                                                                                ##STR190##       1383, 1170, 750, 590                                                                  7.53˜7.72(2H, m), 7.87˜8.03(1H,                                   m), 8.07˜8.23(1H, m)*                      39                                                                                ##STR191##               2.67(3H, s), 4.13(3H, s), 7.51˜8.03(3H,                                  m)*                                             41                                                                                ##STR192##       1734, 1375, 1169, 1102                                                                 ##STR193##                                      42                                                                                ##STR194##       1415, 1381, 1371, 1237, 1172, 1151                                                    2.81(3H, s), 7.60˜8.06(3H, m),             43                                                                                ##STR195##       1617, 1383, 1371, 1216, 1173                                                          7.70(1H, dd, J=8.6, 1.0Hz), 7.87(1H, d,                                       J=8.6Hz), 8.08(1H, d, J=1.0Hz)                   44                                                                                ##STR196##       1604, 1380, 1192, 1161, 534                                                           7.86(1H, d, J=8.9Hz), 8.27(1H, dd, J=8.9,                                     2.0Hz), 8.55(1H, d, J=2.0Hz), 8.93(1H, s)*       45                                                                                ##STR197##       1379, 1368, 1314, 1171, 1158                                                          7.50(1H, t, J=7.9Hz), 7.82(1H, d, J=5.6Hz),                                   8.00˜8.28(3H, m)*                          46                                                                                ##STR198##       1375, 1311, 1202, 1169, 1043                                                          7.47˜8.15(5H, m)                           47                                                                                ##STR199##               7.35˜7.90(5H, m)                           48                                                                                ##STR200##       1457, 1395, 1214, 1166                                                                7.05˜7.14(2H, m), 8.21˜8.24(1H,                                   m)                                               50                                                                                ##STR201##       1625, 1590, 1522, 1377, 1175                                                          8.00˜8.98(4H, m)                           52                                                                                ##STR202##       1590, 1374, 1178, 765                                                                 7.36˜7.78(9H, m)                           54                                                                                ##STR203##       2945, 2941, 1453, 1373, 1161                                                          1.23˜2.50(10H, m), 3.39˜3.65(1H,                                  m)*                                              63                                                                                ##STR204##       1479, 1380, 1166, 1000, 548                                                           7.37(1H, dd, J=8.6, 1.3Hz), 7.44(1H, s),                                      7.84(1H, d, J=8.6Hz), 8.04(1H, d, J=1.3Hz)       64                                                                                ##STR205##       1493, 1454, 1390, 1167                                                                7.32˜7.53(2H, m), 7.62(1H, s),                                          7.82˜7.97(1H, m)                           65                                                                                ##STR206##       2968, 2935, 1503, 1465, 1375, 1167                                                    1.59(3H, d, J=7.3Hz), 4,11˜4.44(1H,                                     m), 7.44˜7.64(2H, m), 7.83˜7.94(1                                 H, m), 8.19˜8.26(1H, m)*                   66                                                                                ##STR207##               7.42˜8.06(4H, m)                           67                                                                                ##STR208##       1473, 1389, 1177, 533                                                                 7.51˜8.11(4H, m)*                          68                                                                                ##STR209##       1737, 1371, 1329, 1201, 1174                                                           ##STR210## 90.4˜ 93.2 (dec.)              70                                                                                ##STR211##       1575, 1530, 1394, 1384, 1174                                                          7.47˜7.69(3H, m)*                                                                   116.0˜ 116.9                   71                                                                                ##STR212##       1520, 1395, 1231, 1148                                                                7.31˜7.67(4H, m)                           72                                                                                ##STR213##       1396, 1178, 1049                                                                      7.73(1H, s) 101.3˜ 103.0                   73                                                                                ##STR214##       1488, 1384, 1174, 570                                                                 7.26˜7.92(3H, m)*                                                                   90.0˜ 92.0                     74                                                                                ##STR215##       2948, 1436, 1417, 1166                                                                1.79˜1.94(4H, m), 2.62˜2.85(4H,                                   m), 7.55(1H, s)*                                 75                                                                                ##STR216##       1398, 1242, 1182, 1147, 534                                                           7.31˜7.70(9H, m)*                                                                   76.2˜ 77.4                     76                                                                                ##STR217##       1526, 1389, 1370, 1179, 570, 538                                                      7.42˜8.27(4H, m)*                          77                                                                                ##STR218##               6.96(1H, d, J=5.6Hz), 7.66˜7.77(1H,                                     m)*                                              78                                                                                ##STR219##       1478, 1419, 1383, 1178                                                                7.42˜8.41(4H, m)*                          79                                                                                ##STR220##               7.45˜7.85(3H, m), 8.40˜8.50(1H,                                   m)*                                              80                                                                                ##STR221##       1381, 1161, 1086, 775                                                                 7.24˜7.85(4H, m)*                          82                                                                                ##STR222##       1377, 1172, 1164, 762, 567                                                            2.58(3H, s), 7.46˜8.25(4H, m)*             83                                                                                ##STR223##       1510, 1377,  1348, 1175, 578                                                          4.09(3H, s), 7.36˜7.74(4H, m)              97                                                                                ##STR224##       1533, 1385, 1168, 1077                                                                7.49˜7.71(3H, m), 7.86(1H,                                                          82.1˜ 82.9                     98                                                                                ##STR225##       1507, 1501, 1391, 1225, 1139                                                          7.38˜7.88(4H, m)*                                                                   88.3˜ 91.6                     101                                                                               ##STR226##               7.46(1H, d, J=1.7Hz), 7.61(1H, d, J=1.7Hz)*      102                                                                               ##STR227##               7.46˜7.99(4H, m)*                          __________________________________________________________________________     NMR data marked with asterisks (*) were measured in CDCl.sub.3 -         

                                      TABLE 13                                    __________________________________________________________________________    QSO.sub.2 NHCH.sub.2 COOEt                                                    Ex.                                   M.P.                                    No.                                                                              Q              IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                            __________________________________________________________________________    97                                                                                ##STR228##    3340, 1742, 1357, 1204, 1161                                                          1.18(3H, t, J=7.3Hz), 3.96(2H, d, J=5.6Hz),                                   4.10(2H, q, J=7.3Hz), 5.51(1H, t, J=5.6Hz),                                   7.35˜7.73(4H m)                                                                     81.2˜ 81.5                        98                                                                                ##STR229##    3184, 1738, 1364, 1225                                                                1.00(3H, t, J=7.1Hz), 3.87(2H, q, J=7.1Hz),                                   3.92(2H, d, J=5.9Hz), 7.45˜7.90(4H, m),                                 9.03(1H, t, J=5.9Hz)                                                                      130.4˜ 134.1                      99                                                                                ##STR230##    3197, 1737, 1366, 1229, 1162                                                          1.19(3H, t, J=7.1Hz), 4.02(2H, d, J=6.6Hz),                                   4.10(2H, d, J=7.1Hz), 5.64(1H, t, J=6.6Hz),                                   7.24˜7.63(3H, m)                                                                    129.4˜ 130.6                      100                                                                               ##STR231##    3295, 1732, 1366, 1232, 1147                                                           ##STR232## 132.9˜ 133.4                      101                                                                               ##STR233##    3236, 1731, 1365, 1233, 1148                                                          1.20(3H, t, J=7.1Hz), 4.02(2H, d, J=4.9Hz),                                   4.11(2H, q, J=7.1Hz), 5.62(1H, t, J=4.9Hz),                                   7.38(1H, d, J=1.7Hz), 7.51(1H, d,                                                         167.3˜ 169.2                      102                                                                               ##STR234##    3202, 1739, 1371, 1228, 1171                                                          1.00(3H, t, J=6.9Hz), 3.90(2H, q, J=6.9Hz),                                   3.99(2H, d, J=6.6Hz), 7.44˜7.89(4H, m),                                 9.39(1H, t, J=6 6Hz)                                                                      135.6˜ 147.8                      __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________    QSO.sub.2 NHCH.sub.2 CO.sub.2 H                                               Ex.                                      M.P.                                 No.                                                                              Q                 IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                         __________________________________________________________________________    63                                                                                ##STR235##               3.74(2H, s), 7.48˜8.27(4H, m),                                          8.55(1H, bs)                                                                              210.1˜ 213.3                   64                                                                                ##STR236##       3270, 1732, 1394, 1354, 1260, 1160                                                    3.76(2H, d, J=5.9Hz), 7.38˜8.09(4H,                                     m), 8.65(1H, t, J=5.9Hz), 12.74(1H,                                                       193.0˜ 205.0                   65                                                                                ##STR237##       3312, 2980, 2968, 1726, 1321, 1143                                                    1.45(6H, d, J=7.3Hz), 3.72(2H, d, J=4.3Hz),                                   3.84˜4.17(1H, m), 7.42˜8.30(4H,                                   m), 8.61(1H, t, J=4.3Hz)                                                                  110.0˜ 115.5                   66                                                                                ##STR238##       3354, 1730, 1421, 1361, 1214, 1164, 1122                                              3.73(2H, s), 7.57˜8.25(4H,                                                          141.3˜ 144.5                   67                                                                                ##STR239##       3304, 1725, 1709, 1487, 1353, 1249, 1160                                              3.86(2H, d, J=5.9Hz), 7.57˜81.9(4H,                                     m), 8.81(1H, t, J=5.9Hz)                                                                  149.1˜ 153.3                   68                                                                                ##STR240##       3294, 1735, 1158                                                                       ##STR241## 125.0˜ 126.9                   69                                                                                ##STR242##       3280, 1734, 1372, 1347, 1312, 1255, 1167                                              3.72(2H, d, J=5.3Hz), 7.61(1H, s), 8.55(1H,                                   t, J=5.3Hz), 12.85(1H, bs)                                                                200.5˜ 202.0                   70                                                                                ##STR243##       3275, 1718, 1364, 1161                                                                3.82(2H, d, J=5.9Hz), 7.53(1H, s), 7.63(1H,                                   d, J=1.6Hz), 7.99(1H, bs), 8.95(1H, t,                                        J=5.9Hz)    194.2˜ 196.4                   71                                                                                ##STR244##       1717, 1709, 1437, 1369, 1150                                                          3.82(2H, d, J=5.9Hz), 7.36˜7.80(4H,                                     m), 8.95(1H, t, J=5.9Hz).                                                                 153.4˜ 156.1                   72                                                                                ##STR245##       3340, 1718, 1321, 1252, 1153, 1141, 1130                                              3.79(2H, d, J=5.9Hz), 8.17(1H, s), 8.72(1H,                                   t, J=5.9Hz), 12.82(1H, bs)                                                                203.5˜ 205.2                   73                                                                                ##STR246##       3344, 1713, 1498, 1341, 1247, 1163                                                    3.88(2H, d, J=6.3Hz), 7.43˜7.82(3H,                                     m), 8.98(1H, t, J=6.3Hz)                                                                  194.0˜ 201.0                   74                                                                                ##STR247##       3315, 3201, 2433, 1752, 1443, 1326, 1187,                                             1.50˜1.98(4H, m), 2.40˜2.88(4H,                                   m), 3.59(2H, d, J=4.9Hz), 7.26(1H, s),                                        8.08(1H, t, J=4.9Hz)                                                                      141.2˜ 143.2                   75                                                                                ##STR248##       3265, 1716, 1352, 1236, 1169, 1139                                                    3.74(2H, s), 7.08˜7.81(9H, m),                                          8.72(1H, bs)                                                                              151.4˜ 153.7                   76                                                                                ##STR249##       3290, 1742, 1375, 1255, 1173, 1118                                                    3.82(2H, d, J=5.9Hz), 7.45˜8.16(4H,                                     m), 8.84(1H, t, J=5.9Hz), 12.72(1H,                                                       129.7˜ 134.2                   77                                                                                ##STR250##       3306, 3117, 1732, 1546, 1424, 1412, 1336,                                              ##STR251## 167.4˜ 169.4                   78                                                                                ##STR252##       3264, 1725, 1420, 1350, 1249, 1160                                                    3.74(2H, d, J=5.6Hz), 7.45˜8.31(4H,                                     m), 8.60(1H, t, J=5.6Hz), 12.51(1H,                                                       126.0˜ 129.5                   79                                                                                ##STR253##       1747, 1589, 1367, 1198                                                                4.30(2H, d, J=5.9Hz), 7.21˜8.34(4H,                                     m), 9.94(1H, t, J=5.9Hz)                                                                  212.4 (dec.)                         80                                                                                ##STR254##       3265, 1717, 1362, 1248, 1159                                                          3.83(2H, d, J=5.9Hz), 7.22˜7.84(4H,                                     m), 8.85(1H, t, J=5.9Hz), 12.66(1H,                                                       222.9˜ 227.1                   81                                                                                ##STR255##       3290, 1707, 1560, 1338, 1167                                                          2.16(3H, s), 2.43(3H, s), 3.65(2H, d,                                         J=6.3Hz), 8.27(1H, t, J=6.3Hz), 12.45(1H,                                     bs)         247.0 (dec.)                         97                                                                                ##STR256##       3312, 1719, 1353, 1249, 1165                                                          3.77(2H, s), 7.49˜7.79(3H, m),                                          8.04(1H, s), 8.79(1H, bs)                                                                 186.5                                98                                                                                ##STR257##       3230, 1709, 1368, 1238, 1173                                                          3.82(2H, d, J=5.9Hz), 7.44˜7.73(4H,                                     m), 8.88(1H, t, J=5.9Hz)                                                                  179.4˜ 183.0                   99                                                                                ##STR258##       3280, 1716, 1369, 1238, 1168                                                           ##STR259## 222.9˜ 227.1                   100                                                                               ##STR260##       3338, 1731, 1365, 1234, 1166                                                          3.83(2H, bs), 7.63(2H, s), 8.14(1H, s),                                       9.00(1H, bs)                                                                              210.4˜ 212.0                   101                                                                               ##STR261##       3238, 1717, 1369, 1171, 1151                                                          3.86(2H, d, J=6.3Hz), 7.66(1H, d, J=1.7Hz),                                   8.07(1H, d, J=1.7Hz), 9.15(1H, t,                                                         239.1˜ 241.3                   102                                                                               ##STR262##       3247, 1716, 1373, 1239, 1173                                                          3.89(2H, d, J=6.3Hz), 7.50˜7.91(4H,                                     m), 9.30(1H, t, J=6.3Hz)                                                                  162.0˜ 178.1                   __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________    QSO.sub.2 NHCH.sub.2 CONH.sub.2                                               Ex.                                   M.P.                                    No.                                                                              Q              IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                            __________________________________________________________________________    82                                                                                ##STR263##    3434, 3308, 3188, 1703, 1366, 1155                                                    2.46(3H, s), 3.67(2H, d, J=4.6Hz), 7.10(1H,                                   bs), 7.30(1H, bs), 7.53˜8.16(5H,                                                    180.4˜ 181.1                      83                                                                                ##STR264##    3392, 1672, 1522, 1354, 1333, 1153, 1139                                              3.60(2H, s), 4.10(3H, s), 7.05(1H, bs),                                       7.20(1H, bs), 7.53˜8.16(5H,                                                         162.0˜ 163.1                      __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________     ##STR265##                                                                   Ex.                                      M.P.                                 No.                                                                              Q                 IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                         __________________________________________________________________________    63                                                                                ##STR266##       3320, 1800, 1769, 1458, 1370, 1230                                                     ##STR267## 249.6 (dec.)                         64                                                                                ##STR268##       3110, 1791, 1751, 1745, 1381, 1180                                                    4.76(2H, s), 7.50˜7.82(1H, m),                                          8.11(1H, dd, J=7.6, 1.3Hz), 8.57(1H, s),                                      12.79(1H, bs)                                                                             221.0 (dec.)                         65                                                                                ##STR269##       3140, 1791, 1757, 1459,  1346, 1177                                                   1.43(6H, d, J=6.9Hz), 3.63˜3.96(1H,                                     m), 7.47˜7.61(1H, m), 8.07˜8.31(1                                 H, m), 12.84(1H, bs)                                                                      191.3˜ 195.7                   66                                                                                ##STR270##       3120, 1756, 1465, 1366, 1175, 1164                                                    4.76(2H, s), 7.60˜8.38(4H, m),                                          13.01(1H, bs)                                                                             232.1˜ 233.5                   67                                                                                ##STR271##       3180, 1782, 1755, 1455, 1372, 1170                                                    4.95(2H, s), 7.56˜8.32(4H, m),                                          12.92(1H, bs)                                                                             222.8 (dec.)                         68                                                                                ##STR272##       3220, 1756, 1726, 1376, 1173                                                           ##STR273## 204.7 (dec.)                         69                                                                                ##STR274##       1793, 1473, 1392, 1191, 1174                                                          4.69(2H, s), 8.07(1H, s), 12.78(1H,                                                       203.0 (dec.)                         70                                                                                ##STR275##       3292, 1795, 1765, 1464, 1381, 1185, 1176                                              4.74(2H, s), 7.73(1H, d, J=1.7Hz), 8.06.about                                 .8.09(2H, m) 12.87(1H, bs)                                                                211.6 (dec.)                         71                                                                                ##STR276##       1795, 1759, 1460, 1384, 1149                                                          4.83(2H, s), 7.43˜7.89(4H, m),                                          12.96(1H, bs)                                                                             212.8˜ 219.9 (dec.)            72                                                                                ##STR277##       3350, 1793, 1764, 1458, 1362, 1174                                                    4.87(2H, s), 8.44(1H, s), 12.88(1H,                                                       242.0 (dec.)                         73                                                                                ##STR278##       3289, 1795, 1770, 1492, 1458, 1359, 1180, 1156,                                       4.97(2H, s), 7.55˜7.88(3H, m),                                          13.01(1H, bs)                                                                             254.0  (dec.)                        74                                                                                ##STR279##       3157, 1794, 1765, 1376, 1352, 1161                                                    1.50˜1.94(4H, m), 2.46˜2.94(4H,                                   m), 4.65(2H, s), 7.72(1H, s), 12.61(1H,                                                   245.0˜ 246.8                   75                                                                                ##STR280##       1786, 1750, 1446, 1370, 1348, 1178                                                    4.37(2H, s), 7.13˜7.90(9H, m),                                          12.82(1H, bs)                                                                             183.8 (dec.)                         76                                                                                ##STR281##       3130, 1790, 1759, 1383, 1182                                                          4.73(2H, s), 7.57˜8.15(4H, m),                                          12.81(1H, bs)                                                                             230.5˜ 223.8                   77                                                                                ##STR282##       3107, 1755, 1537, 1469, 1423, 1376, 1248,                                             4.66(2H, s), 7.21(1H, d, J=5.6Hz), 8.16(1H,                                   dd, J=5.6, 4.3Hz).                                                                        194.4 (dec.)                         78                                                                                ##STR283##       3268, 1790, 1765, 1459,  1348, 1178, 1160                                             4.93(2H, s), 7.50˜7.73(2H, m),                                          8.04˜8.29(2H, m), 12.82(1H,                                                         244.0˜ 246.0                   79                                                                                ##STR284##       1790, 1763, 1460, 1348, 1182                                                          4.68(2H, s), 7.59˜7.70(2H, m),                                          8.14˜8.40(2H, m), 12.68(1H,                                                         710.0 (dec.)                         80                                                                                ##STR285##       3215, 1744, 1456, 1332, 1162                                                          4.77(2H, s), 7.30˜7.91(4H, m),                                          12.85(1H, bs)                                                                             210.9 (dec.)                         81                                                                                ##STR286##       3180, 1761, 1535, 1371, 1170                                                          2.19(3H, s), 2.54(3H, s), 4.68(2H, s),                                        12.64(1H, bs), 12.75(1H, bs)                                                              250.0 (dec.)                         97                                                                                ##STR287##       3319, 1794, 1766, 1461, 1163                                                          4.73(2H, s),  7.63(1H, d, J=8.6Hz), 7.85(1H,                                  d, J=8.6Hz), 8.05(1H, s), 8.12(1H,                                                        246.8˜ 247.7                   98                                                                                ##STR288##       1735, 1397, 1228, 1173                                                                4.88(2H, s), 7.56˜7.90(4H, m),                                          13.04(1H, bs)                                                                             195˜ 198                       99                                                                                ##STR289##       3330, 1792, 1764, 1456, 1174                                                           ##STR290## 219.5˜ 222.3                   100                                                                               ##STR291##       3084, 1749, 1388, 1266, 1182                                                          4.81(2H, s), 7.70(1H, s), 7.72(1H, s),                                        8.22(1H, s) >240 (dec.)                          101                                                                               ##STR292##       3568, 1752, 1382, 1244, 1177                                                          4.84(2H, s), 7.76(1H, d, J=1.6Hz), 8.17(1H,                                   d, J=1.6Hz), 13.15(1H, bs)                                                                220 (dec.)                           102                                                                               ##STR293##       3110, 1752, 1239, 1178, 1174                                                          4.83(2H, s), 7.60˜7.99(4H,                                                          161.6˜ 179.3                   __________________________________________________________________________

Formulation F (Capsules)

Compound 38, 250 g of weight, 730 g of lactose and 20 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous.The mixture was then filled in No. 1 hard gelatin capsule at 200 mg eachto obtain capsule preparation.

Formulation G (Tables)

Compound 34, 300 g of weight, 550 g of lactose, 120 g of potato starch,15 of polyvinyl alcohol and 15 g of magnesium stearate were weighed. Theweighed amount of compound 34, lactose and potato starch were mixeduntil accomplishing homogeneity. Then aqueous solution ofpolyvinylalcohol was added to the mixture and granulated by wet process.The granules were then dried, mixed with magnesium stearate and pressedinto tablets, each weighing 200 mg.

Formulation H (Powder)

Compound 46, 200 g of weight, 790 g of lactose and 10 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous toobtain 20% powder preparation.

Formulation I (Suppositories)

Compound 44, 100 g or weight were weighed and ground by a mortar untilthe compound became fine powder. Then 180 g of polyethylene glycol 1500and 720 g of polyethylene glycol 4000 were added to the compound andmelted. The mixture was then pressed at 1 g each to obtain suppositorypreparation.

What is claimed is:
 1. A sulfonylglycine derivative represented by theformula (IV):

    Q--SO.sub.7 NHCH.sub.7 CO--R                               (IV)

wherein R represents a hydroxy group, an alkoxy group or an amino groupwhich may be substituted with an alkoxycarbonyl group, Q represents abenzo[b]furan-2-yl group which may be substituted by one or moresubstituents which are the same or different and selected from the groupconsisting of a halogen atom, a lower alkyl group, a nitro group, acyano group, an optionally protected carboxy group, an optionallyprotected carboxymethyl group, a halogenated lower alkyl group, a loweralkylthio group, a lower alkylcarbonyl group, a lower alkoxy group, alower alkylsulfinyl group, a lower alkylsulfonyl group, an optionallyprotected hydroxy group other than a lower alkoxy group, an optionallyprotected amino group, a carbamoyl group and a phenyl group.
 2. Asulfonylglycine derivative as claimed in claim 1, wherein saidsubstituents are 1 to 3 halogen atoms. .[.3. A sulfonylglycinederivative represented by the formula (IV):

    Q--SO.sub.2 NHCH.sub.2 CO--R                               (IV)

where R represents a hydroxy group, an alkoxy group or an amino groupwhich may be substituted with an alkoxycarbonyl group, Q represents athiazolyl group which may be substituted by one or more substituentswhich are the same or different and selected from the group consistingof a halogen atom, a lower alkyl group, a nitro group, a cyano group, anoptionally protected carboxy group, an optionally protectedcarboxymethyl group, a halogenated lower alkyl group, a lower alkylthiogroup, a lower alkylcarbonyl group, a lower alkoxy group, a loweralkylsulfinyl group, a lower alkylsufonyl group, an optionally protectedhydroxy group other than a lower alkoxy group, an optionally protectedamino group, and a carbamoyl group..]. .[.4. A sulfonylglycinederivative as claimed in claim 1 wherein Q represents a pyridyl groupwhich may be substituted..].
 5. A sulfonylglycine derivative as claimedin claim .[.1.]. .Iadd.18 .Iaddend.wherein Q represents an indolyl groupwhich may be substituted. A sulfonylglycine derivative as claimed inclaim .[.1.]. .Iadd.18 .Iaddend.wherein Q represents a benzothiazolylgroup which may be substituted.
 7. A sulfonylglycine derivative asclaimed in claim .[.1.]. .Iadd.18 .Iaddend.wherein Q represents abenzisothiazolyl group which may be substituted.
 8. A sulfonylglycinederivative as claimed in claim .[.1.]. .Iadd.18 .Iaddend.wherein Qrepresents a coumarinyl group which may be substituted.
 9. Asulfonylglycine derivative as claimed in claim .[.1.]. .Iadd.18.Iaddend.wherein Q represents a chromonyl group which may besubstituted.
 10. A sulfonylglycine derivative as claimed in claim.[.1.]. .Iadd.18 .Iaddend.wherein Q represents a benzimidazolyl groupwhich may be substituted.
 11. A sulfonylglycine derivative as claimed inclaim .[.1.]. .Iadd.18 .Iaddend.wherein Q represents a benzotriazolylgroup which may be substituted.
 12. A sulfonylglycine derivative asclaimed in claim .[.1.]. .Iadd.18 .Iaddend.wherein Q represents abenzisoxazolyl group which may be substituted. .[.13. A sulfonylglycinederivative represented by the formula (IV):

    Q--SO.sub.2 NHCH.sub.2 CO--R                               (IV)

wherein R represents a hydroxy group, an alkoxy group or an amino groupwhich may be substituted with an alkoxycarbonyl group, Q represents afuryl group, a pyridyl group, an indolyl group, a benzothiazolyl group,a benzisothiazolyl group, a benzothienyl group, a coumarinyl group, achromonyl group, a benzimidazolyl group, a benzotriazolyl group or abenzisoxazolyl group any one of which may be substituted by one or moresubstituents which are the same or different and selected from a groupconsisting of a halogen atom, a lower alkyl group, a nitro group, acyano group, an optionally protected carboxy group, an optionallyprotected carboxymethyl group, a halogenated lower alkyl group, a loweralkylthio group, a lower alkylcarbonyl group, a lower alkoxy group, alower alkylsulfinyl group, a lower alkylsulfonyl group, an optionallyprotected hydroxy group other than a lower alkoxy group, an optionallyprotected amino group, a carbamoyl group and a phenyl group, or Qrepresents a benzo[b]furan-2-yl group which may be substituted by one ormore substituents which are the same or different and are selected fromthe group consisting of a halogen atom, a cyano group, an optionallyprotected carboxymethyl group, a halogenated lower alkyl group, a loweralkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, a carbamoyl group and a phenyl group..].
 14. A sulfonylglycinederivative as claimed in claim .[.13.]. .Iadd.18.Iaddend., wherein Qrepresents a furyl group, a benzothienyl group or a benzo[b]furan-2-ylgroup.
 15. A sulfonylglycine derivative as claimed in claim 14, whereinQ represents a benzo[b]thien-2-yl group which may b substituted.
 16. Asulfonylglycine derivative as claimed in claim 14, wherein Q representsa benzo[b]furan-2-yl group which may b substituted.
 17. Asulfonylglycine derivative as claimed in claim 16, wherein the saidsubstituents are 1 to 3 halogen atoms. .Iadd.18. A sulfonylglycinederivative represented by the formula (IV):

    Q--SO.sub.2 NHCH.sub.2 CO--R                               (IV)

where R represents a hydroxy group, an alkoxy group or an amino groupwhich may be substituted with an alkoxycarbonyl group, Q represents afuryl group, an indolyl group, a benzothiazolyl group, abenzisothiazolyl group, a benzothienyl group, a coumarinyl group, achromonyl group, a benzimidazolyl group, a benzotriazolyl group or abenzisoxazolyl group any one of which may be substituted by one or moresubstituents which are the same or different and are selected from thegroup consisting of a halogen atom, a lower alkyl group, a nitro group,a cyano group, an optionally protected carboxymethyl group, ahalogenated lower alkyl group, a lower alkylthio group, a loweralkylcarbonyl group, a lower alkoxy group, a lower alkylsulfinyl group,a lower alkylsulfonyl group, an optionally protected hydroxy group otherthan a lower alkoxy group, an optionally protected amino group, acarbamoyl group, and a phenyl group, or Q represents abenzo[b]furan-2-yl group which may be substituted by one or moresubstituents which are the same or different and are selected from thegroup consisting of a halogen atom, a cyano group, an optionallyprotected carboxymethyl group, a halogenated lower alkyl group, a loweralkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, a carbamoyl group and a phenyl group. .Iaddend.